AMERICAN COLLEGE OF TOXICOLOGY
November 6-9, 2011
Arizona Biltmore Resort & Spa
2400 E. Missouri
Phoenix, AZ 85016
PROGRAM
32ND ANNUAL MEETING
TABLE OF CONTENTS
Table of Contents .......................................................................................................................................... 1
General Information .................................................................................................................................... iv
Program-at-a-Glance.................................................................................................................................... vi
SUNDAY, November 6, 2011 ......................................................................................................................... 1
Schedule of Events .................................................................................................................................... 1
Continuing Education Courses .................................................................................................................. 2
Study Director Training .........................................................................................................................................2
Nonclinical ADME in Safety Assessment ...............................................................................................................3
Biomarkers in Nonclinical Toxicology....................................................................................................................4
The Changing Role of the Toxicologist in Today’s Pharma: In-Licensing, Ad-comms and Trends in the CROs ....5
Clinical Pathology For The Toxicologist – Looking Beyond the Asterisks ..............................................................6
Study Monitoring at CROs. Keeping Your Sanity and Achieving the Best Product (Best Practices, Pitfalls, And
Keys to Efficiency) .................................................................................................................................................7
Cardiovascular Toxicology Continuing Education Tutorial ....................................................................................8
Opportunities During Change: Advancing Your Toxicology Career in an Uncertain Market ................................9
Introduction to Translational Imaging in Nonclinical Safety Assessment: A Technology and Applications
Perspective ..........................................................................................................................................................10
Interpreting Stress-Related Findings in Pre-Clinical Safety Assessments ............................................................11
WELCOME BUFFET ................................................................................................................................ 12
MONDAY, November 7, 2011 ..................................................................................................................... 13
Schedule of Events .................................................................................................................................. 13
Plenary Lecture: “GLP Modernization: What Does This Mean To You” ................................................. 14
Morning Symposia .................................................................................................................................. 15
Evolving Issues and Approaches to Regulatory Biocompatibility Assessment in the Development of Medical
Devices ................................................................................................................................................................15
Update on Preclinical Oncology Drug Development ...........................................................................................16
What Animal Model Do You Use For Your Study? ..............................................................................................17
ACT Awards Luncheon ............................................................................................................................ 18
Afternoon Symposia................................................................................................................................ 19
Safety Evaluation of Drug-Device Combination Products With Dual Efficacy and Drug-Drug Combinations
Intended for Co-Administration ..........................................................................................................................19
Potential Utility of Humanized Mouse Models in Drug Development ................................................................20
Ocular Toxicity From Systemically Administered Xenobiotics: Considerations in Drug Development ................21
ACT Member’s Meeting .......................................................................................................................... 22
ACT RECEPTION ....................................................................................................................................... 23
TUESDAY, November 8, 2011...................................................................................................................... 24
Schedule of Events .................................................................................................................................. 24
Plenary Lecture: “Climate Change and Speaking Truth to Power: How Sound Science Can Inform Wise
Policy” ..................................................................................................................................................... 25
Morning Symposia .................................................................................................................................. 26
In Silico Toxicity Predictions: Fact or Fiction ...................................................................................... 26
The Use of Imaging Biomarkers in Nonclinical Research and Development and in Clinical Trials ......................27
The ELSIE Database: Extractables And Leachables Knowledge Sharing .............................................................28
AMERICAN COLLEGE OF TOXICOLOGY
32ND ANNUAL MEETING
2011
Oligonucleotide Therapeutics: Current Issues in Nonclinical Safety Testing and Regulatory Perspectives ........29
2012 Program Planning Meeting ............................................................................................................ 30
Afternoon Symposia................................................................................................................................ 31
Alternative Approaches For Preclinical Development of Biotherapeutic Products .............................................31
Physiological Biomarkers in Toxicology and Safety Pharmacology ....................................................................32
New Data on The Toxicology of Petroleum Hydrocarbons .................................................................................33
New Drug Application (NDA): Industry and Regulatory Perspectives on The Make-Up and Evaluation of The
Nonclinical Components Supporting Approval ...................................................................................................34
POSTER SESSION & SAGE RECEPTION ..................................................................................................... 36
Wednesday, November 9, 2011 ................................................................................................................. 37
Schedule of Events .................................................................................................................................. 37
Plenary Lecture: “ FALLOUT FROM FALLOUT: RISKS VERSUS HYPE” ...................................................... 38
Morning Symposia .................................................................................................................................. 39
Advances in Assessing The Safety of New Food Additives and Food Contaminants ...........................................39
FDA-Industry Dialogue on The Draft Guidance on Assessment of Abuse Potential of Drugs..............................40
Animal Welfare: Where Science Meets Ethics ...................................................................................................41
Afternoon Symposium ............................................................................................................................ 42
Hot Topics! ..........................................................................................................................................................42
INSTRUCTIONS FOR PREPARING POSTERS .................................................................................................. 43
SYMPOSIA & CONTINUING EDUCATION COURSE CHAIRS AND SPEAKERS ................................................. 44
ABSTRACTS .................................................................................................................................................. 57
ABSTRACT AUTHORS ................................................................................................................................. 112
THANK YOU TO OUR EXHIBITORS ............................................................................................................. 116
AMERICAN COLLEGE OF TOXICOLOGY 2011 COUNCIL ............................................................................. 119
ACT COMMITTEES – 2011 ......................................................................................................................... 123
ACT PAST PRESIDENTS .............................................................................................................................. 127
32ND ANNUAL MEETING SPONSORS – 2011 ........................................................................................... 128
32nd ANNUAL MEETING CONSULTANT SPONSORSHIP ............................................................................ 130
ACT CORPORATE MEMBERSHIP - 2011 ..................................................................................................... 132
UPCOMING MEETINGS ............................................................................................................................. 133
AMERICAN COLLEGE OF TOXICOLOGY
32ND ANNUAL MEETING
2011
Welcome to the 32nd Annual Meeting
of the
American College of Toxicology
GENERAL INFORMATION
SOCIAL ACTIVITIES
SUNDAY
Buffet
dinner
followed
by
entertainment by the Native
American Dancers
Pre-Registration Required
MONDAY
TUESDAY
ACT Awards Luncheon
ACT Members Meeting
ACT Reception
Poster Session & Wine and Cheese
Reception
AWARDS
ACT DISTINGUISHED SCIENTIST AWARD
(FORMERLY THE DISTINGUISHED SERVICE AWARD)
At the ACT Awards Luncheon held on Monday, this
award will be presented to a member of the toxicology
community who has made “outstanding contributions
to toxicology and its relationship to the regulation of
chemicals and the improvement of public health”. The
recipient of this award will also make a presentation.
Selection of the recipient of this award was done by
the Awards Committee and endorsed by the Council.
ACT SERVICE AWARD
PLENARY LECTURE SERIES (8:00 AM)
MONDAY
CT Viswanathan
CT Viswanathan & Associates INC
“GLP Modernization: What Does
This Mean to You”
TUESDAY
(FORMERLY LIFETIME ACHIEVEMENT AWARD)
This award is given at the discretion of the ACT Council
to recognize an individual for long term dedication to
the American College of Toxicology. Criteria for
receiving this award include but are not limited to
service to the College (e.g. councilor, officer,
committee member), frequent participation and
contribution to the Annual Meeting (speaker,
chairperson, organizing committee) and longstanding
support of the College's activities.
YOUNG PROFESSIONAL AWARD
The criteria for selection is:
An ACT member in good standing; No more than 10
years of graduate/postgraduate experience; active and
outstanding service to the College, including serving as
an officer, councilor, committee member, and/or
frequent participation and contribution at the Annual
Meeting or any other College activity (i.e., speaker,
chairperson, organizing committee, etc.).
MARSHALL STEINBERG MEMORIAL PRIZE
Richard CJ Somerville
Distinguished Professor Emeritus &
Research Professor
This prize is given at the discretion of the International
Pharmaceutical Excipients Council (IPEC) Foundation
Board of Directors to reward those individuals who
AMERICAN COLLEGE OF TOXICOLOGY
WEDNESDAY
32ND ANNUAL MEETING
2011
Scripps Institution of
Oceanography
University of California San Diego
“Climate Change and Speaking
Truth to Power: How Sound
Science Can Inform Wise Policy”.
have made outstanding contributions in the area of
safety and toxicology for excipients. This prize
recognizes achievements in the field of pharmaceutical
excipients that includes but is not limited to: (1)
research that contributes to the safety of excipients;
(2) investigations that establish test methods and
standards that enhance the safety of excipients; (3)
studies that support the development of new
excipients or novel uses for existing excipients that
provide or assure greater safety in their use in
pharmaceuticals; and (4) toxicology research that
improves the overall safety of excipients and/or
finished pharmaceuticals.
Jacqueline P Williams
Research Professor
University of Rochester School of
Medicine and Dentistry
Dept. of Radiation Oncology
“Fallout From Fallout: Risks
Versus Hype”
FURST AWARD
Through a generous contribution from Dr. Arthur
Furst, the American College of Toxicology was able to
institute the Furst Award, an award of $2000 for the
best student paper presented at each Annual Meeting
of the College. Students will present their papers to
the Committee on Sunday, November 6, 2011.
STUDENT TRAVEL AWARD
This year the College will provide travel awards in the
amount of $1000.00 to some students attending and
presenting a poster at the Annual Meeting. Any
student receiving a travel award is also eligible for the
Furst Award.
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND ANNUAL MEETING
PROGRAM-AT-A-GLANCE
7:00
8:00
9:00
10:00
11:00
12:00
1:00
1:30
2:00
3:00
4:00
5:00
Sunday
November 6
Monday
November 7
Tuesday
November 8
Wednesday
November 9
Continental Breakfast
Continental Breakfast
Continental Breakfast
Continental Breakfast
PLENARY LECTURE
PLENARY LECTURE
PLENARY LECTURE
Symposium VII:
In Silico Toxicity Predications: …..
Symposium VIII:
The Use of Imaging Biomarkers in…..
Symposium IX:
The ELSIE Database: ………
Symposium X:
Oligonucleotide Therapeutics:Current….
Symposium XV:
Advances Assessing Sfty in New Food…
Symposium XVI:
GFA=Industry Dialogue on …..
Symposium XVII:
Animal Welfare: Where Science Meets
Ethics
Course No.1:
Study Director Training
Course No.2:
Nonclinical ADME in Sfty Assess.
Course No.3:
Biomarkers In Nonclinical Tox.
Course No.4:
Changing Role of Toxicologist…
Course No.5:
Clinical Pathology for The Toxicologist
Lunch on your Own
Course No.6:
Study Monitor at CROs
Course No.7:
Cardiovascular Toxicology…
Course No.8:
Opportunities During Change:…
Course No.9:
Intro to Translational Imaging…
Course No.10:
Interpreting Stress-Related Findings in
Pre-Clinical Safety Assessments
Symposium I:
Evolving Issues & Approaches to….
Symposium II:
Unpdate Preclin Oncology Drug Development
Symposium III:
What Animal Model Do You Use for
Your Study?
2011 Program ad hoc
Planning Meeting
- OPEN to ALL –
SIGN UP PLEASE!!
Awards Ceremony &
Luncheon
Symposium IV:
Safety Evaluation of Drug-Device…..
Symposium V:
Potential Utility of Humanized Mouse
Symposium VI:
Ocular Toxicity From Systemically….
Symposium XI:
Alternative Approaches for……
Symposium XII:
Physiological Biomarkers in Tox…..
Symposium XIII:
New Data Tox Petroleum
Hydrocarbons
Symposium XIV:
NDA: Industry & Reg. Perspectives…
5:30
ACT Members Meeting
6:00
6:30
7:00
ACT Social Event
ACT Reception
vi
Poster Session &
Reception
Lunch on your Own
Symposium XVIII:
Hot Topics
AMERICAN COLLEGE OF TOXICOLOGY
32ND ANNUAL MEETING
0
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SUNDAY, NOVEMBER 6, 2011
7:00 am – 8:00 am
Continental Breakfast
Frank Lloyd Wright
Prefunction Central
7:00 am – 5:00 pm
Registration Desk Open
Frank Lloyd Wright
Registration
8:00 am – 11:30 pm
Continuing Education Courses
Course No.1
Grand Canyon
Course No.2
McArthur 3
Course No.3
Frank Lloyd Wright G-H
Course No.4
Frank Lloyd Wright I-J
Course No.5
McArthur 1-2
2:00 pm – 5:00 pm
Exhibit Set-Up
Frank Lloyd Wright A-F
2:00 pm – 5:00 pm
Poster Set-Up
Frank Lloyd Wright A-F
1:00 pm – 4:30 pm
Continuing Education Courses
7:00 pm – 9:30 pm
Course No.6
Grand Canyon
Course No.7
McArthur 3
Course No.8
Frank Lloyd Wright G-H
Course No.9
Frank Lloyd Wright I-J
Course No.10
McArthur 1-2
Buffet & The Native American
Dancers
(Pre-Registration)
1
Gold Room
SUNDAY
SCHEDULE OF EVENTS
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSES
CONTINUING EDUCATION COURSE NO.1
STUDY DIRECTOR TRAINING
Grand Canyon
This continuing education course is intended to provide an introduction to a study director’s responsibilities and
review both logistical-, regulatory-, and scientific-related aspects of toxicology studies. The course will focus on
the practicalities of study director responsibilities for study conduct, oversight, protocols, and final reports. This
course will also review the evolution and scope of the GLP regulations and what a study director should do/not do
during an FDA inspection, as well as how to manage challenges a study director can encounter in toxicology
studies. Scientific aspects of toxicology studies will also be reviewed including animal models and studies used for
the assessment of immune function (immunotoxicology). This is an excellent course for newer study directors, as
well as an informative review and refresher for the more experienced study directors.
Course Manuals are supported in part by an educational donation provided by:
Barbara Mounho, Amgen Inc.
SESSION CHAIR
BATTELLE MEMORIAL INSTITUTE
8:00 am
WELCOME AND INTRODUCTION
Barbara Mounho, Director, Global Regulatory Affairs Biosimilar Policy and
Strategy, Amgen, Inc.
8:15 am
STUDY DIRECTOR GUIDELINES FOR SUCCESS
Carol S. Auletta, Director, Program Management, Huntingdon Life Sciences
8:50 am
OVERVIEW AND HISTORY OF GLPs
Melissa Reinert, Senior Quality Assurance Auditor, Biotechnical Services, Inc.
9:25 am
TOXICOLOGY STUDY REPORTS – PRINCIPLES AND PRACTICES FOR
GENERATING QUALITY DOCUMENTS
Mark D. Walker, DVM, Vice President of Toxicology, Frontier BioSciences,
Inc.
10:00 am
REFRESHMENT BREAK
10:20 am
ANIMAL MODELS FOR TOXICOLOGY STUDIES
Laura Conour, Director, Research Resources, Princeton University
10:55 am
IMMUNOTOXICOLOGY
Thomas Kawabata, Ph.D., Pfizer, Inc.
2
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSE NO.2
NONCLINICAL ADME IN SAFETY ASSESSMENT
McArthur 3
Course Manuals are supported in part by an educational donation provided by:
Alan Brown, Integrated Nonclinical Development
Solutions, Inc.
Robert Guttendorf, Aclairo Pharmaceutical
Development Group, Inc.
SESSION CHAIRS:
BATTELLE MEMORIAL INSTITUTE & ACLAIRO PDG., INC.
8:00 am
ABSORPTION AND PHARMACOKINETICS
Robert J. Guttendorf, Sr. Consultant, DMPK, Aclairo Pharmaceutical
Development Group, Inc.
9:00 am
DISTRIBUTION AND ELIMINATION
Gordon R. Loewen, Sr. Director, Drug Metabolism & Pharmacokinetics,
Infinity Pharmaceuticals
9:45 am
REFRESHMENT BREAK
10:00 am
METABOLISM AND DRUG INTERACTIONS
Richard E. Ridgewell, Associate Director, Drug Metabolism, Covance
Laboratories Inc.
10:45 am
INTEGRATION OF ADME AND TOXICOLOGY DATA FOR SAFETY
ASSESSMENT
Alan P. Brown, Sr. Toxicology Consultant, Integrated Nonclinical
Development Solutions, Inc.
3
SUNDAY
ADME/PK/TK is integral to the drug discovery and development process at all stages. An understanding of the
dispositional characteristics of a new molecular entity (NME) is crucial to the optimal design of safety studies
(general tox, DART, safety pharmacology, carcinogenicity) and risk assessment. This course will review the science
underpinning each aspect of ADME. Relevant theory, technologies, and methodologies will be presented, but the
emphasis will be on practicality and real world utilization of ADME/PK/TK data for decision making and problem
solving (candidate selection, dose selection, species selection, etc.). The integration of ADME data with
pharmacodynamic and toxicology results for safety assessment will be discussed. This will be supported with case
studies of small molecule and large biologic NMEs. This course will be of primary interest to members working
within the pharmaceutical industry, however many of the concepts will be of relevance to other industries.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
CONTINUING EDUCATION COURSE NO.3
BIOMARKERS IN NONCLINICAL TOXICOLOGY
Frank Lloyd Wright G-H
Novel toxicity biomarkers for monitoring drug-induced tissue injury have been useful tools for pharmaceutical
candidate development and regulatory applications. This Continuing Education course will provide attendees with
an overview of novel toxicity biomarker development, preclinical evaluation and qualification, and translation to
clinical settings. Topics include the qualification of transcriptional biomarker sets for safety purposes; the
evaluation and qualification of miRNAs as both sensitive and specific biomarkers of tissue toxicity; and a
presentation on translational challenges related to liver toxicity biomarkers. The program will close with an update
from the FDA on biomarker qualifications (renal and others) and insight on the use of biomarkers in the regulatory
setting.
Course Manuals are supported in part by an educational donation provided by:
Warren Glaab, Merck and Company
Capt. Mark Seaton, US FDA
SESSION CHAIRS:
BATTELLE MEMORIAL INSTITUTE
8:00 am
NONCLINICAL BIOMARKERS OF TOXICITY: AN OVERVIEW
Richard S. Paules, Acting Chief, Laboratory of Toxicology & Pharmacology
Head, Environmental Stress and Cancer Group Director, NIEHS Microarray
Core Facility, NIEHS, NIH
8:50 am
PLASMA microRNAs AS SENSITIVE AND SPECIFIC BIOMARKERS OF TISSUE
INJURY: FROM PRECLINICAL UTILITY TO CLINICAL TRANSLATION
Warren E. Glaab, Safety Assessment, Merck and Co.
9:40 am
REFRESHMENT BREAK
10:00 am
TRANSLATIONAL ASPECTS OF LIVER TOXICITY BIOMARKERS
Alison Harrill, Hamner Center for Drug Safety Sciences, The Hamner
Institutes for Health Sciences
10:50 am
FDA UPDATE ON NONCLINICAL BIOMARKER QUALIFICATIONS
Patricia P. Harlow, Pharmacologist, US FDA
4
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSE NO.4
Frank Lloyd Wright I-J
The pharmaceutical industry is in a rapid state of change. Corporate consolidation, restructuring and changing
business models have had a major impact on how pre-clinical development is managed. Traditional internal
resources such as drug discovery and safety assessment laboratories are now being reduced or replaced with
partnerships, in-licensed molecules and out-sourced services. As the business models continue to evolve in an
effort to be better, faster and more cost-effective, it can be expected that drug development will become more
“virtual” in nature with increased reliance on shared resources amongst partner-companies and the reliance on
CRO providers. The nature of such models relies not only on savvy business agreements, but also on in-depth due
diligence review of available data. And as cutting edge science and the most current technology in drug discovery
continues to identify novel targets, it can be expected that the potential for new drug candidates to be subject to
an FDA advisory committee will be even higher. As such, these changes within the pharmaceutical industry will
impact the role of the toxicologist and how pre-clinical safety assessment is ultimately managed. This CE course
will present how toxicology has been impacted by these changes and address the skills necessary to be successful
in the field.
Course Manuals are supported by an educational donation provided by:
Stephen Barat, Forest Research Institute
Shana Azri-Meehan, Forest Research Institute
SESSION CHAIRS
BATTELLE MEMORIAL INSTITUTE
8:00 am
WELCOME AND INTRODUCTION
Shana Azri-Meehan, Senior Principal Scientist, Forest Research Institute
8:15 am
THE CHANGING FACE OF THE PHARMACEUTICAL INDUSTRY: A SWEEPING
PERSPECTIVE
William J. Brock, President, Brock Scientific Consulting
9:00 am
THE ROLE OF THE CRO IN A CHANGING MARKET
Fred Kirchner, Executive Director, Toxicology, Pathology, Safety
Pharmacology, Covance Labs
9:45 am
REFRESHMENT BREAK
10:00 am
HOW TO CONDUCT DUE DILIGENCE--ASPECTS FOR THE TOXICOLOGIST TO
CONSIDER WHEN REVIEWING IN-LICENSING OPPORTUNITIES
Stephen A. Barat, Director, Forest Research Institute
10:45 am
THE CHANGING ROLE OF THE TOXICOLOGIST IN FDA ADVISORY
COMMITTEE MEETINGS
Shana Azri-Meehan, Senior Principal Scientist, Forest Research Institute
5
SUNDAY
THE CHANGING ROLE OF THE TOXICOLOGIST IN TODAY’S PHARMA: INLICENSING, AD-COMMS AND TRENDS IN THE CRO S
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
CONTINUING EDUCATION COURSE NO.5
CLINICAL PATHOLOGY F OR THE TOXICOLOGIST – LOOKING BEYOND THE
ASTERISKS
McArthur 1-2
Clinical pathology is often one of the key endpoints in safety assessment of drugs and chemicals. Clinical pathology
data are screening tools to identify general metabolic or pathologic processes and target organs and may
occasionally serve as pharmacodynamic markers. It is important for scientists involved in safety assessment
to understand factors that may impact clinical pathology data and their interpretation.
This course
will describe key study design factors that affect data quality and interpretation and look beyond statistical
significance to integrate findings with other findings with other clinical and pathology endpoints; common patterns
of change will be highlighted. In addition, the course will discuss the value and appropriate use in safety
assessment of several more recently developed clinical pathology biomarkers.
Course Manuals are supported by an educational donation provided by:
Robert Hall, Covance Laboratories
Mingyi Trimble, Covance Laboratories
SESSION CHAIRS:
BATTELLE MEMORIAL INSTITUTE
8:00 am
WELCOME AND INTRODUCTION
Mingy Trimble, Study Director, Covance Laboratories
8:15 am
STUDY DESIGN CONSIDERATIONS (WHAT, WHEN, HOW, WHY) AND DATA
INTERPRETATION CONCEPTS (IS IT REAL? IS IT BAD?)
Robert Hall, Clinical Pathologist, Covance Laboratories Inc.
9:00 am
HEMATOLOGY
Nancy Everds, Clinical Pathologist, Amgen Inc.
9:45 am
REFRESHMENT BREAK
10:00 am
CLINICAL CHEMISTRY, URINALYSIS, AND URINE CHEMISTRY – BASIC
CONCEPTS AND SPECIAL CONSIDERATIONS
Niraj Tripathi, Clinical Pathologist, Covance Laboratories Inc.
10:45 am
COMMONLY USED BIOMARKERS
Jacqueline Tarrant, Scientist – Pathologist, Genentech
6
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSE NO.6
Grand Canyon
With the increased emphasis on outsourcing toxicology studies to specialty Contract Research Organizations (CRO),
toxicologists are being asked to monitor studies being conducted outside of their organizations. In this capacity,
they must ensure that the toxicology program is conducted properly and in a cost effective manner. This presents
a particular challenge to the toxicologist because many toxicologists have no training in managing these types of
programs. This course will provide the participants with the tools they need to succeed in this endeavor.
Specifically, this course will discuss what factors the toxicologist needs to consider when selecting a CRO including
bid solicitation and bid analysis (cheapest is not always best). It will also discuss the interactions between the Study
Monitor and the CRO before, during and after the study. It includes a CRO’s Study Director’s perspective of what
makes an effective team between the Study Monitor and the Study Director. It will conclude with a discussion of
the legal obligations between you and the CRO. This course is a must for any toxicologist who is responsible for
outsourcing toxicology studies, no matter what type of company he/she works for.
Course Manuals are supported by an educational donation provided by:
BATTELLE MEMORIAL INSTITUTE
1:00 pm
WELCOME AND INTRODUCTION
Steve Snyder, Outsourcing Support Services, Inc.
Paul Roney, INC Research
SESSION CHAIRS:
Paul L. Roney, Senior Consultant Toxicology, INC Research
1:05 pm
OUTSOURCING NONCLINICAL SAFETY STUDIES: BEST PRACTICES FOR
SELECTING A CRO
Jon Daniels, Executive Vice President & Senior Toxicologist, Intrinsik Health
Sciences, Inc.
1:35 pm
AN INDUSTRY VETERAN’S GUIDE TO EFFECTIVE STUDY MONITORING
Steve Snyder, President, Outsourcing Support Services, Inc.
2:05 pm
THE SPONSOR/CRO RELATIONSHIP IN NON-CLINICAL SAFETY TESTING
Susan McPherson, Manager Toxicology, Charles River Laboratories, Inc.
2:35 pm
REFRESHMENT BREAK
2:50 pm
QA ASSESSMENT
William T. Reinholt, Manager, Quality Assurance, MPI Research
3:20 pm
LEGAL AND FINANCIAL ARRANGEMENTS (BALANCING ACT BETWEEN YOU,
THE ATTORNEYS AND SARBANES-OXLEY)
Clynn Wilker, Senior Director, Toxicology, Ardea Biosciences
3:50 pm
Q&A
7
SUNDAY
STUDY MONITORING AT CROS. KEEPING YOUR SANITY AND ACHIEVING
THE BEST P RODUCT (BEST P RACTICES , PITFALLS, A ND K EYS TO
EFFICIENCY)
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
CONTINUING EDUCATION COURSE NO.7
CARDIOVASCULAR TOXICOLOGY C ONTINUING EDUCATION TUTORIAL
McArthur 3
This tutorial is intended to approach cardiovascular toxicology by presentations from a group of scientists with
extensive experience with cardiovascular assessments. It includes an overview of commonly used methods and
explores the issues relative to the proper use and evaluation of the data. Further, relatively new and advanced
techniques will be described as will the impact of pre-clinical data upon clinical design and decision making. The
final lecture will suggest a path forward for cardiovascular toxicology including the utilization of approaches that
facilitate the choice of the safest and/or most predictable drug candidates.
Course Manuals are supported by an educational donation provided by:
BATTELLE MEMORIAL INSTITUTE
1:40 pm
Brian Roche, Battelle Memorial Institute
Craig Hassler, Battelle Memorial Institute
SESSION CHAIRS:
1:00 pm
2:20 pm
3:00 pm
3:15 pm
3:55 pm
BASIC FUNCTIONS AND MEASUREMENT OF THE CARDIOVASCULAR
SYSTEM FOR TOXICOLOGICAL STUDIES
Brian Roche, Associate Manager Safety Pharmacology Battelle Memorial
Institute
WHAT PROPERTIES AND WHAT MAGNITUDE CHANGE WILL LEAD TO
CARDIAC MORBIDITY AND MORTALITY
Robert L. Hamlin, The Ohio State University College of Veterinary Medicine.
QTest Labs
ADVANCED TECHNIQUES AND THEIR APPLICATION TO THE ASSESSMENT
OF CARDIOVASCULAR TOXICOLOGY
Periannan Kupasami, The Ohio State University College of Medicine
REFRESHMENT BREAK
THE USE OF PRECLINICAL QT DATA TO IMPACT EARLY CLINICAL STUDY
DESIGNS AND DECISION MAKING
Philip Sager, Chair, Scientific Program Committee, Cardiac Safety Research
Consortium and Pharmaceutical/Device Consultant
THE TRANSITION OF ANIMAL BASED CARDIOVASCULAR DATA TO CLINICAL
TRIALS/SUMMARY OF THE CE SYMPOSIUM
Gary A. Gintant, Research Fellow, Chairman, Abbott QT Working Group,
Abbott
8
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
CONTINUING EDUCATION COURSE NO.8
Frank Lloyd Wright G-H
The severity in the economic markets has created uncertainty in many jobs in toxicology, and many toxicologists
are considering transitioning earlier in their career to secure continued employment. The goal of this workshop is
to educate toxicologists on the various options for their career path before migrating to another career choice.
The workshop speakers will include scientists who have made career transitions and have succeeded in their new
position in the pharmaceutical industry, consulting, and CRO industry as well as in the legal profession. The
various speakers will give a brief overview of their day-to-day workload as well as share their career transition
experiences and the lessons learned along the way.
Course Manuals are supported by an educational donation provided by:
Melanie Hartsough, Biologics Consulting
Group, Inc.
L Peyton Myers, US FDA
SESSION CHAIRS:
BATTELLE MEMORIAL INSTITUTE
1:00 pm
WELCOME AND INTRODUCTION
L. Peyton Myers, Pharmacology/Toxicology Drug Reviewer, US FDA
1:15 pm
WHAT CAN TOXICOLOGY CERTIFICATIONS DO FOR YOU (E.G., DABT, FATS,
ERT)?
Hanan Ghantous, Supervisory Toxicologist, US FDA, CDER, OND, OAP
1:45 pm
LIFE AS A TOXICOLOGIST IN SMALL, MID-SIZE AND LARGE COMPANIES
Drew A. Badger, Director, Regulatory Affairs, Amgen Inc.
2:15 pm
EXPECTATIONS AND CHALLENGES OF STARTING A CRO
Gary R. Burleson, and Florence G. Burleson, President and Executive Vice
President, BRT – Burleson Research Technologies, Inc.
2:45 pm
REFRESHMENT BREAK
3:00 pm
TRANSITIONING FROM AN 8-5 JOB TO CONSULTING
Hilary Sheevers, President, CEO, Aclairo PDG., Inc.
3:30 pm
SCIENTISTS OUTSIDE THE BOX: INFORMATION, INTELLECTUAL PROPERTY
AND LEGISLATION
Kathy McGown, Director, Knowledge Resources, FoxKiser
4:00 pm
Q&A DISCUSSION
9
SUNDAY
OPPORTUNITIES DURING CHANGE: ADVANCING Y OUR T OXICOLOGY
CAREER IN AN UNCERTAIN MARKET
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSE NO.9
INTRODUCTION TO TRANSLATIONAL IMAGING IN NONCLINICAL SAFETY
ASSESSMENT: A TECHNOLOGY AND APPLICATIONS PERSPECTIVE
Frank Lloyd Wright I-J
Clinical imaging is a staple in contemporary clinical medicine with continuing advances improving early recognition
of disease as well as facilitating monitoring of disease progression or regression. Accordingly, clinical imaging is
growing in popularity with drug developers as a means for assessing drug distribution or monitoring efficacious
response to a novel therapeutic in living patients. Historically, imaging applications in nonclinical animal species
have been limited by the ability to scale the technology to the smaller size of the animals typically used in
nonclinical safety studies. These limitations are largely a thing of the past. A great opportunity exists to leverage
the advances in clinical imaging to improve the translatability of nonclinical safety assessments. The goal of this
session is to introduce nonclinical safety scientists to the array of available imaging technologies, potential
applications of those technologies, and future opportunities for improving on contemporary safety assessment
paradigms.
Course Manuals are supported by an educational donation provided by:
Syril Pettit, HESI
G. Allan Johnson, Duke University Medical Center
SESSION CHAIRS:
BATTELLE MEMORIAL INSTITUTE
1:00 pm
AN INTRODUCTION TO INTEGRATION OF CLINICAL IMAGING TO
NONCLINICAL SAFETY ASSESSMENT
Brian R. Berridge, Director, Regulatory & Discovery Pathology,
GlaxoSmithKline Safety Assessment
1:40 pm
MOLECULAR IMAGING FOR TOXICOLOGICAL RESEARCH
Serguei Liachenko, Director, Bio-Imaging, US FDA, NCTR
2:20 pm
ULTRASOUND IMAGING IN DRUG DISCOVERY AND SAFETY SCIENCES
Robert W. Coatney, Director, Comparative Biology and Medicine,
GlaxoSmithKline
3:00 pm
REFRESHMENT BREAK
3:10 pm
MAGNETIC RESONANCE MICROSCOPY
G. Allan Johnson, Charles E. Putman Professor of Radiology, Physics, and
Biomedical Engineering, Duke University Medical School, Center for In Vivo
Microscopy
3:50 pm
DIGITAL SUBTRACTION ANGIOGRAPHY AND MICROCT FOR SMALL
ANIMAL TOXICOLOGY
Cristian Tudorel Badea, Associate Professor, Radiology, Duke University
Medical School, Center for In Vivo Microscopy
10
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
CONTINUING EDUCATION COURSE NO.10
McArthur 1-2
Stress can confound the interpretation of clinical and anatomical findings in pre-clinical safety assessments. Stress
can be the result of physiological responses to perturbations of homeostasis, including those effects caused by
changes in either neural or endocrine responses. With regards to pre-clinical safety assessments, the issue of
stress becomes distinguishing primary test-article effects from secondary effects. Not only is the stress response
highly variable (acute vs. chronic), but the complexity and bidirectional nature of the various organ systems and
the hypothalamic-pituitary-adrenal axis can make interpretation of some stress-related findings difficult. This
session will provide a basic understanding of the potential sources of stress in toxicology studies and the common
stress-associated organ system findings. By focusing on the major organ systems impacted by stress such as the
nervous, endocrine, and immune system, the presentations will describe the pathophysiological pathways
involved and include some case-based examples of the types of parameters in toxicology studies that are
influenced by stress. Because no single parameter can indicate that the animal was stressed, investigators are
often reliant on a weight-of-evidence approach to interpreting a set of findings as stress-related. The aim of the
topics covered is to provide the toxicologist with an understanding of the stress response and the findings
commonly associated with a stress response that can be used in a weight-of evidence approach to facilitate the
interpretation of the findings in the correct context of the study objectives.
Course Manuals are supported by an educational donation provided by:
Paul Snyder, Purdue University
SESSION CHAIR:
BATTELLE MEMORIAL INSTITUTE
1:00 pm
WELCOME AND INTRODUCTION
Paul Snyder, Professor Comparative Pathology, Purdue University
1:10 pm
STRESS AND THE NERVOUS SYSTEM
Brad Bolon, Associate Professor, The Ohio State University
2:00 pm
STRESS AND THE ENDOCRINE SYSTEM
Tom Rosol, Ohio State University
2:50 pm
REFRESHMENT BREAK
3:00 pm
CLINICAL PATHOLOGY ASPECTS OF STRESS
Nancy Everds, Clinical Pathologist, Amgen Inc.
3:50 pm
STRESS AND THE IMMUNE SYSTEM
Paul W. Snyder, Professor of Pathology, Purdue University
11
SUNDAY
INTERPRETING STRESS-RELATED FINDINGS IN PRE-CLINICAL SAFETY
ASSESSMENTS
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
(CT SOCIAL EVENT
WELCOME BUFFET
WELCOME BUFFET
And the
NATIVE AMERICAN
DANCERS
SUNDAY EVENING, NOVEMBER 6, 2011
7:00 pm - 9:30 pm
GOLD ROOM & PATIO
PRE-REGISTRATION ONLY
12
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
MONDAY, NOVEMBER 7, 2011
SCHEDULE OF EVENTS
Continental Breakfast
FLW- Exhibit Hall
7:00 am – 5:00 pm
Registration Desk Open
FLW Registration
8:00 am - 8:45 am
Plenary Lecture
McArthur 4-7
9:00 am – 12:00 pm
Symposia
Symposium I
Frank Lloyd Wright G-H
Symposium II
Frank Lloyd Wright I-J
Symposium III
McArthur 1-2
9:30 am – 5:00 pm
Exhibits Open
Frank Lloyd Wright A-F
9:00 am – 5:00 pm
Posters Open
Frank Lloyd Wright A-D
ACT Awards Luncheon
McArthur 4-7
12:00 pm – 2:00 pm
2:00 pm – 5:00 pm
Symposia
Symposium IV
Frank Lloyd Wright G-H
Symposium V
Frank Lloyd Wright I-J
Symposium VI
McArthur 1-2
5:30 pm – 7:00 pm
ACT Members Meeting
McArthur 1-2
7:00 pm – 8:30 pm
ACT Reception
Gold Room
13
MONDAY
7:00 am – 8:00 am
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
PLENARY LECTURE: “GLP MODERNIZATION: WHAT DOES THIS MEAN TO YOU”
PLENARY LECTURE
8:00 am – 8:45 am
McArthur 4 - 7
CT Viswanathan, Ph.D.
CT Viswanathan & Associates Inc.
“GLP MODERNIZATION: WHAT
DOES THIS MEAN TO YOU”
Co-Sponsored by Calvert Laboratories, Inc.
14
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
MORNING SYMPOSIA
SYMPOSIUM I
EVOLVING ISSUES AND APPROACHES TO REGULATORY BIOCOMPATIBILITY
ASSESSMENT IN THE DEVELOPMENT OF MEDICAL DEVICES
Frank Lloyd Wright G-H
David Hobson, LoneStar Pharm Tox LLC
Shayne Gad, Gad Consulting Services
SESSION CHAIRS:
9:00 am
INTRODUCTION
Shayne C. Gad, Principal, Gad Consulting Services
9:10 am
BASIC TESTING REQUIREMENTS: ISO AND FDA
Joseph W. Carraway, Director, Toxicology, NAMSA
9:40 am
ANALYTICAL APPROACHES FOR DEGRADATION PRODUCTS, EXTRACTABLES
AND LEACHABLES FROM MEDICAL DEVICES
Michael Shelton, Technical Director, Exova Inc.
10:10 am
REFRESHMENT BREAK
10:30 am
NANOTECHNOLOGY ENABLED DEVICE DESIGN AND SAFETY ASSESSMENT
David W. Hobson, President, LoneStar Pharm Tox, LLC
11:00 am
BIOCOMPATABILITY ASSESSMENT OF ANTIMICROBIAL DEVICES
Shayne C. Gad, Principal, Gad Consulting Services
11:30 am
BIOCOMPATABILITY TESTING OF INJECTABLE MEDICAL DEVICES
Jeff A. Handler, President, JAH Associates, LLC
15
MONDAY
Evolving Issues and Approaches to Regulatory Biocompatibility and Safety Assessment in the Development of
Medical Devices: The development of modern medical devices toxicology is playing an ever increasing role in the
treatment and diagnosis of health conditions that impact virtually every sector of our population. Advancements in
medical device technology involve significant decisions and considerations for safety evaluation from the design
stage through approval and even after market. The increasing use of advanced technologies such as
nanotechnology as well as inclusion of antimicrobial agents and the delivery of active pharmaceutical agents
incorporated with various types of medical devices makes for a device industry that is constantly evolving. This
requires innovative and novel approaches to toxicologic evaluation in addition to traditional biocompatibility tests.
This symposium will provide an overview and update of the current medical device safety assessment picture for
ISO tests and U.S. FDA requirements for a variety of different types of devices as well as present novel
technologies, such as nanotechnology-enabled devices and approaches to medical device biocompatibility and
safety evaluation.
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM II
UPDATE ON PRECLINICAL O NCOLOGY DRUG DEVELOPMENT
Frank Lloyd Wright I-J
Preclinical testing for oncology drugs has become more streamlined with the finalization of the ICH guidance (S9)
on oncology drug development. A successful new oncology drug typically enters patients with limited life
expectancy, and the regulatory path of a small number of preclinical studies is sensible. Over time however, some
drugs or biologics offer good safety and efficacy in much less serious oncology settings, and the needed preclinical
safety and efficacy studies suddenly increase. This symposium is designed to bring people up to date with drug
development requirements for oncology drugs and biologics. The presentations will then focus on advancing drug
and biologic candidates to less serious indications. Both toxicology (including application of ICH M3 (R2)) and
pharmacology animal models will be presented.
This activity is supported by an educational donation provided by:
Ricerca Biosciences
Vincent Murphy, Array BioPharma, Inc.
Hilary Sheevers, Aclairo PDG, Inc.
SESSION CHAIRS:
9:00 am
WELCOME AND INTRODUCTION
Hillary V. Sheevers, President, CEO, Aclairo PDG, Inc., Vienna, VA
9:15 am
ONCOLOGY PHARMACOLOGY MODELS: VALUABLE PREDICTIVE TOOLS?
Patrice Lee, Senior Director of Pharmacology and Toxicology, Array
BioPharma, Inc.
10:00 am
INTRODUCTION TO THE TOXICOLOGY SIDE OF ONCOLOGY DRUG
DEVELOPMENT
Hilary V. Sheevers, President, CEO, Aclairo PDG, Inc., Vienna, VA and
Vincent A. Murphy, Principal Research Investigator, Array BioPharma, Inc.
10:35 am
REFRESHMENT BREAK
10:50 am
OPTIMIZING LARGE AND SMALL MOLECULE ONCOLOGY DRUG
DEVELOPMENT
Ron Steigerwalt, Preclinical, Director, Amgen Inc.
11:25 am
WHEN TO CHOOSE ICH M3 (R2) FOR THE DEVELOPMENT OF ONCOLOGY
PRODUCTS
Todd Palmby, Pharmacology/Toxicology Reviewer, US FDA, CDER
16
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM III
WHAT ANIMAL MODEL DO YOU USE F OR Y OUR STUDY ?
McArthur 1-2
This activity is supported by an educational donation provided by:
EPL, Inc. & Harlan Laboratories, Inc.
Jerry Hardisty, EPL, Inc.
Robin Guy, Robin Guy Consulting, LLC
SESSION CHAIRS:
9:00 am
WELCOME AND INTRODUCTION
Robin Guy, Robin Guy Consulting, LLC
9:10 am
MOUSE MODELS IN TOXICOLOGY STUDIES
Peter C. Mann, Manager, EPL NorthWest, EPL, Inc.
9:40 am
RAT MODELS IN TOXICOLOGY STUDIES
Prof. Dr. Paul-Georg Germann, Nycomed GmbH
10:20 am
REFRESHMENT BREAK
10:50 am
DOG MODELS IN TOXICOLOGY STUDIES
Klaus Weber, Toxicologic Pathologist, Harlan Laboratories, Inc.
11:20 am
NON-HUMAN PRIMATE MODELS IN TOXICOLOGY STUDIES
Kevin S. McDorman, General Manager, Charles River Pathology Associates
17
MONDAY
It is often a difficult question to determine the correct animal model for your toxicology study. The most
appropriate model may vary depending on the purpose of the toxicology study and the type of test article being
evaluated. This symposium will discuss the selection of animal models for various types of toxicology studies. We
will present the advantages and disadvantages of different species, strains, and stocks of commonly used
laboratory animal models. These would include rat models, mouse models, dog models, and nonhuman primate
models. Each speaker will discuss the available models and present an overview of the most appropriate model for
specific toxicology studies.
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
ACT AWARDS LUNCHEON
12:00 – 2:00 PM
McArthur 4-7
ACT AWARDS LUNCHEON
WELCOME
Russette Lyons, President ACT
STUDENT TRAVEL AWARDS
FURST AWARD
ACT AWARDS
Best Student Poster 2011
MARSHALL STEINBERG MEMORIAL PRIZE
IPEC Foundation Award
ACT PRESIDENT’S AWARD
Best Paper in the International Journal of Toxicology 2011
YOUNG PROFESSIONAL AWARD
Melissa Rhodes, Ph.D., DABT
Sr. Manager, Safety Assessment Project Development
GlaxoSmithKline
ACT SERVICE AWARD
KEYNOTE SPEAKER
David W. Hobson, Ph.D., DABT
Principal
LoneStar PharmTox LLC
ACT DISTINGUISHED SCIENTIST AWARD
Glenn Sipes, Ph.D. Fellow ATS and AAAS
Professor Emeritus, Department of Pharmacology
College of Medicine, University of Arizona
“RECOLLECTION OF 40+ YEARS AS A
TOXICOLOGIST: PEOPLE, PROJECTS, PROGRAMS
AND PROFESSIONALISM”
18
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
AFTERNOON SYMPOSIA
SYMPOSIUM IV
SAFETY EVALUATION OF DRUG-DEVICE COMBINATION PRODUCTS WITH
DUAL EFFICACY AND D RUG-DRUG C OMBINATIONS INTENDED FOR COADMINISTRATION
Frank Lloyd Wright G-H
Lynnda Reid, US FDA
Alan Brown, Integrated Nonclinical Development Solutions
Inc.
SESSION CHAIRS:
Previously, medical products could be readily defined as drugs, biologics or devices, and thereby regulated as such.
However, with the advent of new medical technologies, it has become necessary to define a fourth type of medical
product: combination products. As this name suggests, these are products that consist of a combination of at least
two medical products. Combination products may constitute the use of a device for drug delivery, the use of a
drug or biologic to enhance the efficacy of a medical device, drug-drug combinations. Combination products are
regulated by the US FDA Center or Division determined to have lead regulatory jurisdiction, based on the primary
mode of action or efficacy, but receive consultative input from Center(s) or Division(s) assigned the secondary
regulatory jurisdiction. This symposium will focus on nonclinical safety evaluation of those combination products
in which the device and the drug/biologic components both contribute towards efficacy of the product and on
drug-drug combinations which are intended for co-administration. Examples include drug-eluting vascular stents,
orthopedic devices containing growth factors, and wound healing devices containing antimicrobials.
2:00 pm
INTRODUCTION TO SYMPOSIUM
Alan P. Brown, Senior Toxicology Consultant, Integrated Nonclinical
Development Solutions Inc.
2:30 pm
CDER/CDRH REGULATORY PERSPECTIVE ON COMBINATION PRODUCT
DEVELOPMENT
Kathy Lee, Lead Interdisciplinary Scientist, US FDA-CDER
3:05 pm
PRECLINICAL TESTING REQUIREMENTS FOR STENTS: A CHANGED
REGULATORY LANDSCAPE
John Dooley, Senior Research Fellow, Preclinical R&D, Codman & Shurtleff
(Division of Johnson & Johnson)
3:40 pm
REFRESHMENT BREAK
3:50 pm
REGULATION AND NONCLINICAL ASSESSMENT STRATEGIES FOR DRUGDRUG COMBINATIONS INTENDED FOR CO-ADMINISTRATION
Timothy Hummer, Pharmacology/Toxicology Reviewer, US FDA, CDER
4:25 pm
ROUNDTABLE DISCUSSION
19
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIUM V
POTENTIAL UTILITY OF HUMANIZED MOUSE MODELS IN DRUG
DEVELOPMENT
Frank Lloyd Wright I-J
Alema Galijatovic-Idrizbegovic, Merck & Co.
SESSION CO-CHAIR:
Mark Powley, US FDA
SESSION CHAIR:
2:00 pm
USE OF TRANSGENIC MOUSE MODELS FOR PK AND SAFETY PROFILING OF
COMPOUNDS
Nico Scheer, Head of ADMET R&D, TaconicArtemis GmbH
2:30 pm
MOUSE MODELS WITH HIGHLY HUMANIZED LIVERS: CURRENT
APPLICATIONS AND FUTURE DIRECTIONS
Markus Grompe, Director, Oregon Stem Cell Center, Founder and Chief
Scientific Officer, Yecuris Corporation, Oregon Health & Science University,
Yecuris Corporation
3:05 pm
A HUMAN IMMUNE SYSTEM IN THE MOUSE: CURRENT STATE OF THE
MODEL AND RESEARCH POTENTIAL
Kristina Howard, Commissioner’s Fellow, U.S. FDA
3:40 pm
REFRESHMENT BREAK
3:50 pm
HUMANIZED DRUG METABOLIZING ENZYME MOUSE MODELS–
POTENTIAL APPLICATION IN SAFETY ASSESSMENT
Alema Galijatovic-Idrizbegovic, Associate Director, Merck & Co., Inc.
4:25 pm
FDA PERSPECTIVE ON HUMANIZED ADME MODELS
Mark W. Powley, Pharmacologist, Division of Anti-Viral Products, US FDA
20
MONDAY
Laboratory animals are used in drug development as models of clinical disease, PK/ADME, and toxicology.
Although the goal of non-clinical studies is to provide insight into clinical outcome, species differences can
sometimes result in generation of data with questionable human relevance. To improve the predictive nature of
non-clinical evaluations, more clinically relevant models are needed. Humanized mouse models may potentially
help meet this need. Promising models include mice that express single or multiple human genes involved in drug
metabolism as well as mice with partial to complete human tissues (e.g., liver, immune system, etc.).
This symposium is designed to provide updates concerning recent developments in humanized mouse models.
The target audience includes scientists involved in commercial drug development (e.g., drug metabolism scientists,
toxicologists, etc.) as well as regulators responsible for evaluating data generated during safety testing. Because
these models also have potential applications for toxicology testing in general, the symposium will be of interest to
scientists in the chemical and consumer healthcare industries.
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM VI
OCULAR TOXICITY FROM SYSTEMICALLY ADMINISTERED XENOBIOTICS:
CONSIDERATIONS IN D RUG DEVELOPMENT
McArthur 1-2
This activity is supported by an educational donation provided by:
Christopher Somps, Pfizer, Inc.
William Brock, Brock Scientific Consulting
SESSION CHAIRS:
MPI Research
2:00 pm
OVERVIEW OF SESSION
William J Brock, Principal, Brock Scientific Consulting
2:15 pm
OCULAR TOXICITY IN AN ONCOLOGY THERAPEUTIC: OBSTACLES AND
IMPACT TO DEVELOPMENT
Vince Torti, Pfizer Inc.
2:45 pm
DETECTION OF MICROSCOPIC FINDINGS OF OCULAR TOXICITY
James A. Render, Veterinary Pathologist, NAMSA
3:15 pm
REFRESHMENT BREAK
3:30 pm
FIRST DO NO HARM: NONINVASIVE MEASURES OF STRUCTURE AND
FUNCTION IN OCULAR TOXICOLOGY AND DRUG DISCOVERY
Jeff Jamison, Ophthy-DS, Inc., and MPI Research
4:00 pm
CLINICAL AND NONCLINICAL CORRELATES OF OCULAR TOXICITY:
EVALUATION AND REGULATORY CONSIDERATIONS
Maria I. Rivera, Pharmacologist/Toxicologist, US FDA, CDER
4:30 pm
ROUNDTABLE DISCUSSION
21
MONDAY
The eye is a specialized structure for which irritation or systemic toxicity must be evaluated to determine the
safety of drugs, industrial chemicals, consumer products, etc. Indeed, important diseases such as glaucoma and
macular degeneration are target diseases pharmaceutical companies are devoting resources in order to develop
therapies with fewer side effects. However, for other therapies, ocular toxicity following systemic administration
often results in abandoning a potentially efficacious therapy because of a perceived poor safety profile. Currently
there are several pharmaceuticals on the market that have induced ocular effects in experimental animals
although mechanistic studies have revealed limited concern for humans. In contrast, there are several marketed
therapies that have shown adverse ocular effects that were not seen in nonclinical studies. This symposium will
discuss the design and execution of toxicity studies with the incorporation of current methods for in vivo
assessment of ocular toxicity, and how those methods can detect early changes in the eye that can lead to risk
decisions for further development. In addition, the process of detecting microscopic findings due to ocular toxicity
will be reviewed and include factors such as anatomical differences among laboratory animals, preparation of
globes for examination, and iatrogenic and spontaneous ocular findings. Finally, the correlation between
nonclinical outcomes and clinical evaluations will be discussed in terms of expected therapeutic uses, indications
and the regulatory consequences of ocular effects.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
ACT MEMBER’S MEETING
5:30 PM
McArthur 1-2
MEMBER’S MEETING
(ACT Members Only)
CALL TO ORDER
Russette Lyons, ACT President, Novartis Institutes of Biomedical Research
MINUTES FROM 2011 ANNUAL MEETING
Tracey Spriggs, ACT Secretary, GlaxoSmithKline Consumer Healthcare
OFFICER’S REPORTS
Russette Lyons, Novartis Institutes of Biomedical Research
PRESIDENT-ELECT’S REPORT
David G. Serota, MPI Research
TREASURER’S REPORT
Norman Kim, Biogen Idec, Inc.
MEMBERSHIP COMMITTEE REPORT
James J. Freeman, ExxonMobil Biomedical Sciences, Inc.
COMMITTEE
REPORTS
ACT BUSINESS
PRESIDENT’S REPORT
NOMINATING COMMITTEE REPORT
ACT Past-President, Carol Auletta, Huntingdon Life Sciences
PUBLICATIONS COMMITTEE REPORT
Editor-in-Chief, Mary Beth Genter, University of Cincinnati
22
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
ACT RECEPTION
Music by our own
“JAZZICOLOGY”
CASH BAR
7:00 – 8: 30 pm
GOLD ROOM
23
MONDAY
ACT
RECEPTION
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
TUESDAY, NOVEMBER 8, 2011
SCHEDULE OF EVENTS
7:00 am – 8:00 am
Continental Breakfast
Frank Lloyd Wright A-F
7:00 am – 5:00 pm
Registration Desk Open
Frank Lloyd Wright
Registration
8:00 am -
Plenary Lecture
McArthur 4-7
8:45 am
9:00 am – 12:00 pm
Symposia
Symposium VII
McArthur 1-2
Symposium VIII
Frank Lloyd Wright I-J
Symposium IX
Frank Lloyd Wright G-H
Symposium X
McArthur 3
9:30 am – 4:00 pm
Exhibits Open
Frank Lloyd Wright A-F
9:00 am – 7:00 pm
Posters Open
Frank Lloyd Wright A-D
12:00 pm – 1:30 pm
2011 Program Planning Mtg
Grand Ballroom
2:00 pm – 5:00 pm
5:30 pm - 7:00 pm
Symposia
Symposium XI
McArthur 1-2
Symposium XII
Frank Lloyd Wright I-J
Symposium XIII
Frank Lloyd Wright G-H
Symposium XIV
McArthur 3
Poster Session & Sage
Reception
24
Frank Lloyd Wright A-D
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
PLENARY LECTURE: “CLIMATE CHANGE AND SPEAKING TRUTH TO POWER: HOW SOUND
SCIENCE CAN INFORM WISE POLICY”
PLENARY LECTURE
McArthur 4-7
8:00 am – 8:45 am
Distinguished Professor Emeritus & Research Professor
Scripps Institution of Oceanography
University of California San Diego
“CLIMATE CHANGE AND
SPEAKING TRUTH TO POWER:
HOW SOUND SCIENCE CAN
INFORM WISE POLICY”
CO-SPONSORED BY WIL RESEARCH C OMPANY
25
TUESDAY
Richard C.J. Somerville, Ph.D.
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
MORNING SYMPOSIA
SYMPOSIUM VII
IN SILICO TOXICITY PREDICTIONS: FACT OR FICTION
McArthur 1-2
With the increasing need to deliver new, safer medicines to the market at lower costs for research and
development, the pharmaceutical industry is turning towards the use of cheaper and faster alternatives to
selecting safer drug candidates. In silico models for toxicology have an added appeal in that they can be used even
prior to any chemical synthesis thus avoiding potential known problems from the outset. Along with providing a
basic introduction to computational toxicology, the objectives of this symposium are to provide perspectives from
both industry scientists and FDA regulators on the use of various predictive computational software programs.
Some key topics of discussion will include:
 Which and how many in silico software programs are necessary
 How to use a weight of evidence approach in predictive assessments
 Use of in silico predictions for evaluation of potential genotoxic impurities
 Addressing conflicting outputs from in silico predictions
 Use of computational models for prediction of hepatotoxicity
 Overview of FDA internal process for evaluating structural alerts
 Use of in silico predictions in regulatory decision making
 Limitations of current methodology
This activity is supported by an educational donation provided by:
Holly Dursema, Boehringer-Ingelheim Pharm, Inc.
Lisa Beilke, Gilead Sciences, Inc.
SESSION CHAIRS:
Boehringer Ingelheim & Cubist Pharmaceuticals, Inc.
9:00 am
AN INDUSTRIAL PERSPECTIVE ON MUTAGENICITY MODELING
Catrin Hasselgren, Principal Scientist, AstraZeneca R&D
9:30 am
APPLICATION OF COMPUTATIONAL MODELS FOR TOXICOLOGY IN
PHARMACEUTICAL DEVELOPMENT
Nigel Greene, Associate Research Fellow, Pfizer Inc.
10:05 am
COMPUTATIONAL METHODS BASED ON CHEMICAL STRUCTURE – HOW
USEFUL ARE THEY?
Oliver Flint, Research Fellow, Bristol-Myers Squibb
10:40 am
REFRESHMENT BREAK
10:55 am
REGULATORY UTILITY OF IN SILICO PREDICTIONS: PERSPECTIVES FROM
AN FDA REVIEWER
Mark W. Powley, Pharmacologist, U.S. FDA
11:25 am
THE EXPERIENCE OF THE US FDA/CDER (Q) SAR GROUP: CRITERIA FOR
USING COMPUTATIONAL TOXICOLOGY FOR CDER REGULATORY
DECISIONS
R. Daniel Benz, Computational Toxicologist, US FDA, CDER
26
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
MORNING SYMPOSIA
SYMPOSIUM VIII
THE USE OF IMAGING BIOMARKERS IN N ONCLINICAL RESEARCH AND
DEVELOPMENT AND IN C LINICAL TRIALS
Frank Lloyd Wright I-J
This activity is supported by an educational donation provided by:
G David Young, Flagship Biosciences, LLC
Norman Barlow, Sanofi
SESSION CHAIRS:
Flagship Biosciences & sanofi-aventis US
9:00 am
USE OF IMAGING BIOMARKERS IN DRUG DISCOVERY AND IN RESEARCH
AND DEVELOPMENT PROGRAMS
Norman Barlow, Director, Sanofi
9:40 am
USE OF IMAGING BIOMARKERS IN BASIC RESEARCH AND APPLICATION TO
THE DEVELOPMENT OF PHYSIOLOGICALLY-BASED PHARMACOKINETIC
(PBPK) MODELING FOR RISK ASSESSMENT
O. Joseph Trask, Jr., Head, Cellular Imaging Core, The Hamner Institutes for
Health Sciences
10:20 am
REFRESHMENT BREAK
10:40 am
USE OF DIGITAL PATHOLOGY TO PROVIDE AGGREGATE MEASUREMENTS
OF EFFICACY AND TOXICITY IN NONCLINICAL AND CLINICAL STUDIES
G. David Young, President and Chief Pathologist, Flagship Biosciences, LLC
11:20 am
ANALYZING DISCRETE BIOLOGICAL ENDPOINTS IN SOLID TUMORS
UTILIZING NOVEL DIGITAL PATHOLOGY APPROACHES
Joseph Krueger, Director of Biology, Flagship Biosciences, LLC
27
TUESDAY
A biomarker can be defined as any detectable biologic feature that provides information about its source. As a
general term, it applies to any and all detection modalities. An imaging biomarker is a biologic feature detectable
by imaging modalities. The use of imaging biomarkers in nonclinical research and development and in clinical trials
is becoming a valuable tool in drug development. Before imaging biomarkers can be used as a surrogate endpoint
in clinical trials, they must first be developed and validated in nonclinical models. They are also useful in the
evaluation of efficacy and toxicity in nonclinical animal models. Clinical trials are known to be one of the most
valuable sources of data in evidence-based medicine. For a pharmaceutical, device, or procedure to be approved
for regular use in the U.S., it must be rigorously tested in clinical trials, and demonstrate sufficient efficacy.
Unfortunately clinical trials are also extremely expensive and time consuming. End-points, such as morbidity and
mortality, are used as measures to compare groups within a clinical trial. The most basic endpoint used in clinical
trials, mortality, requires years and sometimes decades of follow-up to sufficiently assess. Morbidity, although
potentially faster to measure than mortality, can also be a very difficult endpoint to measure clinically, as it is often
subjective. These are some of the reasons why biomarkers have been increasingly used in clinical trials to detect
subtle changes in physiology and pathology before they can be detected clinically. The use of surrogate endpoints
(biomarkers) has been shown to significantly decrease the time and resources used in clinical trials. Because
surrogate endpoints allow researchers to assess a marker rather than the patient, it allows participants to act as
their own control, and in many cases allows for easier blinding. In addition to surrogate endpoints, imaging
biomarkers can be used as predictive classifiers, to assist in selecting appropriate candidates for particular
treatment. Predictive classifiers are frequently used in molecular imaging in order to ensure enzymatic response to
therapy.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIUM IX
THE ELSIE DATABASE: EXTRACTABLES AND LEACHABLES KNOWLEDGE
SHARING
Frank Lloyd Wright G-H
Laurie Iciek, MedImmune
William P. Beierschmitt, Pfizer Global R&D
SESSION CHAIRS:
Extractables and leachables (E&L) safety assessments are an essential element of the development process for
pharmaceuticals, biologics and medical devices. Such assessments must be included in applications to health
regulatory authorities. Although safety data on E&L is publicly available in scientific journals, government reports
and databases, this data has never been incorporated into a single database. The Extractables and Leachables
Safety Information Exchange (ELSIE) is a consortium of pharmaceutical, biotech, and medical device companies
that is developing a database that will hold (i) safety information on E&L; and (ii) controlled extraction information
from materials used in container closure systems and devices. The ELSIE database offers many potential benefits
including reducing duplicative safety studies, streamlining the search for safety information for extractables and
leachables, providing information that can be used early in the development process to facilitate the extractables
evaluation process, and reducing the risk of leachables issues arising at the end of development. This symposium
will include an introduction to the ELSIE database initiative, approaches to safety and chemical evaluation of E&L
on which the database is built, and a demonstration of the database. The symposium will be of interest to
toxicologists from the pharmaceutical, biologics and medical device industries; toxicologists from chemical
manufacturers, pharmaceutical packaging engineers, chemists, and regulators.
9:00 am
INTRODUCTION AND BACKGROUND TO ELSIE AND THE ELSIE DATABASE
Laurie Iciek, Principal Toxicologist, MedImmune
9:40 am
SAFETY ASSESSMENT OF EXTRACTABLES AND LEACHABLES: CHALLENGES
AND APPROACHES
William P. Beierschmitt, Associate Research Fellow, Pfizer Global R&D
10:20 am
REFRESHMENT BREAK
10:40 am
THE MATERIAL SELECTION PROCESS FOR DRUG PRODUCT
PACKAGING/DEVICES AND THE ELSIE MATERIALS INITIATIVE
Andrew Feilden, Principal Consultant, Smithers Rapra
11:20 am
DEMONSTRATION OF THE ELSIE DATABASE
Steve Beck, Development Manager, Non-clinical Safety Projects,
GlaxoSmithKline Research & Development
28
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM X
OLIGONUCLEOTIDE THERAPEUTICS: CURRENT ISSUES IN NONCLINICAL
SAFETY TESTING AND REGULATORY PERSPECTIVES
McArthur 3
Oligonucleotides represent a growing class of new therapeutics. To date, oligonucleotides are regulated as small
molecules. The Oligo Safety Working Group (OSWG), an international association of professionals from industry,
academia and regulatory agencies, is evaluating the historical experience with oligonucleotides, with the aim of
achieving an appropriate science-based approach to the toxicity testing of this class of drugs. This symposium will
provide an overview of the structure, properties and applications the main of oligonucleotide subclasses
(antisense, CpG, aptamer, siRNA, microRNA, etc.). The current position of the OSWG with regard to similarities
and differences between the nonclinical safety testing strategies for oligos vs. small molecules vs. biologics will be
presented, as well as the class effects that need to be taken into consideration during study design and
interpretation. As an example, the challenges of advancing inhaled oligonucleotides to the clinic, including the
interpretation of potential adverse effects and their relevance for human safety, will be discussed. The perspective
of the regulatory agencies with regard to oligos in general, the OSWG recommendations, and future directions will
be presented.
This activity is supported by an educational donation provided by:
Timothy McGovern, SciLucent LLC
Cindy Berman, Independent Consultant
SESSION CHAIRS:
ISIS Pharmaceuticals
9:00 am
INTRODUCTION TO OLIGONUCLEOTIDE THERAPEUTICS: STRUCTURE,
FUNCTION, AND APPLICATIONS
Scott P. Henry, ISIS Pharmaceuticals
9:30 am
OLIGOS: AKIN TO SMALL MOLECULES OR BIOLOGICS?
Cindy L. Berman, Independent Consultant
10:00 am
REFRESHMENT BREAK
10:15 am
CLASS EFFECTS AND OTHER SPECIAL CONSIDERATIONS IN SAFETY TESTING
OF OLIGOS
Doug Kornbrust, President, Preclinsight
11:00 am
PRECLINICAL SAFETY ASSESSMENT OF INHALED OLIGONUCLEOTIDES
Nicolay Ferrari, Director Pharmacology, Topigen Pharmaceuticals, part of
the Pharmaxis Ltd. Group
11:30 am
OLIGONUCLEOTIDE THERAPEUTICS: A PHARM/TOX REVIEWER’S
PERSPECTIVE
Robert T. Dorsam, Pharmacologist, US FDA
29
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
12:00 – 2:00 PM
Grand Ballroom
2012 PROGRAM PLANNING MEETING
This is a Program Brainstorming Session. It has been a useful mechanism
for generating ideas for topics and sponsors that the Program Committee
will assess over the coming months.
WHO
Anyone interested in contributing ideas for Symposia, Continuting
Education Courses or Plenary Lectures
WHY
We need and value your input!
HOW
Join the incoming President-Elect and Program Committee Chair, Robin
Guy, for a free brown-bag lunch and let the brainstorming begin!
NOTE
Please sign up for this session at the ACT Registration desk to
ensure that we have enough food for all participants.
30
TUESDAY
WHAT
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
AFTERNOON SYMPOSIA
SYMPOSIUM XI
ALTERNATIVE APPROACHES FOR PRECLINICAL DEVELOPMENT OF
BIOTHERAPEUTIC PRODUCTS
McArthur 1-2
As development of biotherapeutics becomes a more advanced science-based challenge, selection of relevant
animal models, utility of traditional species and alternatives to traditional safety approaches are becoming more
accepted. Assuring safety in humans is the first task of a well designed program but assuring safety and application
to specific patient populations is also essential to targeted therapeutic products. The last ten years has seen
significant advancement of knowledge in development of biotechnology products for treatment of chronic
diseases. As therapies being developed are more sophisticated and generally more specific the need to establish
safety in relevant models has become more of a challenge. Alternatives to traditional safety approaches include
use of homologous proteins, transgenic animals, animal models of disease as well as state of the art non-invasive,
non-terminal technologies such as high resolution imaging and scanning methods. Topics addressed in this
symposium will include general issues related to differences between species that might contribute to species
selection/interpretation, considerations into the development of a homologous protein, and development and
characterization of animal models as relevant species (including KO animals and models of disease). This
symposium will appeal to a broad ACT audience as more companies are developing biologic therapies for use.
This activity is supported by an educational donation provided by:
BASi
WELCOME AND INTRODUCTION
John Devine, BASi
Laura Andrews, Genzyme Corporation
SESSION CHAIRS:
2:00 pm
Laura Andrews, Vice President, Pharmacology/Toxicology Genzyme
Corporation
2:05 pm
THE CHALLENGES AND CONSIDERATIONS OF HOMOLOGOUS MOLECULES
USED IN BIOPHARMACEUTICAL DEVELOPMENT
Donna Lee, Associate Scientist, Safety Assessment, Genentech
2:45 pm
ANIMAL MODELS OF DISEASE: UNIQUE OPPORTUNITIES AND
CHALLENGES
Marque Todd, Regulatory Strategy Lead, Pfizer, Inc.
3:25 pm
REFRESHMENT BREAK
3:40 pm
A TRANSGENIC ANIMAL MODEL AS A USEFUL AND RELEVANT TOOL FOR
SAFETY STUDIES: A CASE PRESENTATION
James Murray, Staff Scientist, Toxicology, Genzyme Corp
4:20 pm
A REGULATORY PERSPECTIVE
M. Stacey Ricci, Senior Toxicologist, US FDA
31
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM XII
PHYSIOLOGICAL BIOMARKERS IN TOXICOLOGY AND SAFETY
PHARMACOLOGY
Frank Lloyd Wright I-J
The development, understanding, and use of biomarkers in drug development and in translational prediction of
later outcomes have long been scientific challenges. In recent years the amount of information in this area of
biomarker development has exploded.
Confident data based decision making in assessing toxicological and
pharmacological safety of new compounds in preclinical models is tightly linked to construction of studies and
models that yield understanding of complex physiological system changes. Physiological parameter assessment
accuracy and predictive parameter utility in making new compound development science based decisions is
critical. Experts will share recent pre-clinical physiological biomarker project experience and recent physiological
study data from a perspective of predictive understanding. Their history of overcoming obstacles in practical
situations will place emphasis on learning where current advanced methods and tools can provide better
understanding and better predictive outcomes.
DATA SCIENCES INTERNATIONAL
WELCOME AND INTRODUCTION
Steven Hachtman, Data Sciences International
Robert Hamlin, Ohio State University
SESSION CHAIRS:
2:00 pm
Steven Hachtman, Director of Application Development, Data Sciences
International
2:10 pm
BIOMARKERS AND TRANSLATION: WHERE ARE PHYSIOLOGICAL
BIOMARKERS EFFECTIVE IN TOXICOLOGY AND SAFETY ASSESSMENT?
Rob Wallis, Executive Director, Early Candidate Leads, Pfizer UK
2:40 pm
CARDIAC PHYSIOLOGY AND CARDIOVASCULAR TOXICITY… DO WE HAVE
MODELS AND MARKERS THAT MAKE SENSE AND WORK
Robert Hamlin, Professor Veterinary Med, Prof. Biomed Eng., Ohio State
University
3:10 pm
IMPROVING CARDIOVASCULAR ASSESSMENT IN CANINE TOXICOLOGY
STUDIES
Pierre Lainee, Principle Scientist R & D, Astra Zeneca, UK
3:40 pm
REFRESHMENT BREAK
4:00 pm
BLOOD PRESSURE ASSESSMENT AS A MARKER IN REGULAR TOXICOLOGY
STUDIES
Mark Niehoff, Study Director Toxicology, Covance Laboratories
4:30 pm
FUNCTIONAL BIOMARKERS IN THE INTEGRATED STUDY DESIGN: WHAT
MAKES SENSE AND WHEN
Ted Baird, Senior Director Safety Pharmacology and Neurobehavioral
Sciences, MPI Research
32
TUESDAY
This activity is supported by an educational donation provided by:
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIUM XIII
NEW DATA ON THE TOXICOLOGY OF PETROLEUM HYDROCARBONS
Frank Lloyd Wright G-H
This activity is supported by an educational donation provided by:
EXXONMOBIL BIOMEDICAL SCIENCES, INC. & AMERICAN PETROLEUM INSTITUTE & ASPHALT INSTITUTE
OVERVIEW OF PETROLEUM SUBSTANCE
Thomas Gray, American Petroleum Institute
SESSION CO-CHAIR:
James Freeman, ExxonMobil Biomedical Sciences, Inc.
SESSION CHAIR:
2:00 pm
James J. Freeman, Distinguished Toxicology Associate, ExxonMobil
Biomedical Sciences, Inc.
2:30 pm
ASSIGNING AN ADI TO WHITE MINERAL OIL: USE OF PHARMACOKINETIC
DATA
Peter J. Boogaard, Senior Toxicologist, Shell International bv
3:00 pm
REFRESHMENT BREAK
3:15 pm
RECENT STUDIES ON THE POTENTIAL CARCINOGENICITY OF ASPHALT
FUMES
Charles R. Clark, Principal Toxicology Consultant, ConocoPhillips Company
3:50 pm
HAZARD CHARACTERIZATION OF COMPLEX PETROLEUM SUBSTANCES
Richard H. McKee, Distinguished Toxicology Associate, ExxonMobil
Biomedical Sciences, Inc.
4:25 pm
PREDICTION OF TOXICITY BASED ON A STATISTICAL ANALYSIS OF
AROMATIC COMPOUNDS PRESENT IN A PETROLEUM STREAM
Mark Nicolich, Consultant in Biostatistics, Cogimet
33
TUESDAY
Petroleum products are complex chemical substances that have a wide range of uses beyond the familiar motor
gasoline. Human or environmental exposure to low levels of petroleum hydrocarbons can occur from various
sources. A number of recent and important toxicology programs on petroleum hydrocarbons are nearing
completion in 2011, encompassing risk assessment, hazard assessment and prediction models, including
 an updated risk assessment for the consumption of mineral hydrocarbons via food
 completion of two plus decades of research on the possible carcinogenicity of asphalt fumes
 approach to the hazard assessment of complex petroleum streams using reference chemicals and readacross for categories of similar compounds
 development of a statistical analysis of chromatography data to predict toxicity endpoints for PAHcontaining petroleum streams.
These topics will be surveyed and summarized in this symposium following a short overview of the nature of
petroleum substances and the general approach to their toxicological evaluation.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIUM XIV
NEW DRUG APPLICATION (NDA): INDUSTRY AND REGULATORY
PERSPECTIVES ON THE MAKE-UP AND EVALUATION OF THE NONCLINICAL
COMPONENTS SUPPORTING APPROVAL
McArthur 3
Timothy McGovern, SciLucent LLC
Norman Kim, Biogen Idec, Inc.
SESSION CHAIRS:
Since 1938, the regulation and control of new drugs in the United States has been the subject of an approved New
Drug Application (NDA). The NDA and Biologics Licence Application (BLA) are the vehicles through which sponsors
formally propose that the Food and Drug Administration (FDA) approve a new pharmaceutical drug or biologic for
sale and marketing in the U.S. This symposium will concentrate on small molecules. The NDA should provide
sufficient information to permit FDA reviewers to reach the following key decisions:
- The safety and efficacy of the drug in its proposed use(s), and whether benefits of the drug outweigh the risks.
- The appropriate wording of the drug's proposed labeling (package insert).
- The adequacy of the methods in the manufacture and the controls used to maintain the drug's identity, strength,
quality, and purity.
The data gathered from the animal studies and human clinical trials during the lengthy development cycle under
an Investigational New Drug (IND) become an integral part of the NDA. The conduct of proper nonclinical and
clinical studies to generate adequate data that demonstrate the safety and efficacy of a drug is imperative, as is
the manufacture and formulation of drug substance and drug product is equally important. Given the importance
of an NDA document, this symposium reviews the current thought process on nonclinical aspects of the NDA from
an industry perspective and from within the Office of New Drugs (OND) under the Center for Drug Evaluation and
Research (CDER) at the FDA. Various steps during this process (IND packages, pre-NDA meeting, format and
content of NDA per electronic Common Technical Document (eCTD), NDA submission process, Refusal to File,
review cycles, advisory committees, labeling process and post-approval commitments) will be discussed. The
interactions within a company and a reviewing division, consulting divisions if applicable, and the relevant Office of
Drug Evaluation (ODE) level will be described and presentations will include examples. Additionally, the session
will discuss the history of drug approval process, the impact of the NDA process since the enactment of the
Prescription Drug User Fee Act (PDUFA) in 1997, and potential changes in the future. A Q&A session will follow the
presentations.
2:00 pm
INTRODUCTION
Norman Kim, Director, Pharmacotoxicology, Biogen Idec and Timothy J.
McGovern, Consultant, SciLucent LLC
2:05 pm
INDUSTRY VIEW POINT OF NONCLINICAL ISSUES IN DRUG DEVELOPMENT
AND NDA
Clynn Wilker, Ardea Biosciences
2:40 pm
IND AND NDA REVIEW PROCESS – PERSPECTIVES FROM A PRIMARY
REVIEWER
Amy Ellis, Pharm/Tox Reviewer, US FDA, CDER, OND
3:15 pm
3:30 pm
4:05 pm
REFRESHMENT BREAK
NDA PROCEDURES – SECONDARY REVIEW PERSPECTIVES
Lynnda Reid, Supervisory Pharmacologist, US FDA, CDER, OND
NONCLINICAL REGULATORY & SAFETY OVERVIEW FOR NONPRESCRIPTION
(OVER THE COUNTER) PRODUCTS AT THE FDA
Wafa A. Harrouk, Senior Pharmacology/Toxicology Reviewer, US FDA. CDER,
34
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
OND, ODEIV
4:40 pm
DISCUSSIONS, Q&A
TUESDAY
35
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
POSTER SESSION & SAGE RECEPTION
5:30 – 7:00
Frank Lloyd Wright A-D
POSTER SESSION
AND SAGE
RECEPTION
36
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
WEDNESDAY, NOVEMBER 9, 2011
SCHEDULE
7:00 am – 8:00 am
Continental Breakfast
Frank Lloyd Wright
Prefunction
7:00 am – 4:00 pm
Registration Desk Open
Frank Lloyd Wright
Registration
8:00 am - 8:45 am
Plenary Lecture
Frank Lloyd Wright F
9:00 am – 12:00 pm
Symposia
Frank Lloyd Wright A-B
Symposium XVI
Frank Lloyd Wright I-J
Symposium XVII
Frank Lloyd Wright G-H
Symposia
Symposium XVIII
4:30 pm
Close
37
Frank Lloyd Wright F
WEDNESDAY
1:30 pm – 4:30 pm
Symposium XV
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
PLENARY LECTURE: “ FALLOUT FROM FALLOUT: RISKS VERSUS HYPE”
PLENARY LECTURE
Frank Lloyd Wright F
8:00 am – 8:45 am
Jacqueline P. Williams, Ph.D.
Research Professor
University of Rochester School of Medicine & Dentistry
Department of Radiation Oncology
“FALLOUT FROM FALLOUT:
RISKS VERSUS HYPE”
38
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
MORNING SYMPOSIA
SYMPOSIUM XV
ADVANCES IN ASSESSING THE SAFETY OF NEW FOOD A DDITIVES AND
FOOD C ONTAMINANTS
Frank Lloyd Wright A-B
The safety evaluation of a new food additive and food contaminants is a complicated, time consuming and
expensive process. The aim of this symposium is to explore how progress in our understanding of structureactivity relationships and computational toxicology methods can serve to facilitate food safety evaluations and
reduce the need for extensive animal testing. Approaches to evaluating chemical structures and functional groups
are continuously evolving. This session will provide updates on refinements to the Cramer et al. (1978) Decision
Tree (DT) and application of the tiered Threshold of Toxicological Concern (TTC) approach. In addition, recent
advances in the use of computational toxicology tools for the evaluation of quantitative structure-activity
relationships (QSAR) of botanically-derived food additives will be discussed. Computational toxicology employing
QSAR modeling is an evidence-based predictive method that is currently being used by regulatory agencies for risk
assessment and scientific decisions to support toxicological endpoints of interest. The current status of how
regulatory agencies (e.g. FDA) use QSAR as a decision support tool, in conjunction with other information for a
weight-of-evidence approach, will be addressed. This symposium will provide a thorough overview of both
traditional (DT and TTC) and contemporary (computational modeling) approaches to structure-activity assessments
and their potential application for safety evaluation of direct food additives and contaminants.
Richard Lane, PepsiCo
Kimberly Ehman, Toxicology Regulatory Services
SESSION CHAIRS:
PEPSICO INC.
9:00 am
STRUCTURE-BASED THRESHOLD OF TOXICOLOGICAL CONCERN IN RISK
ASSESSMENT
Susan P. Felter, Proctor & Gamble Company
9:35 am
REDEFINING THE CRAMER DECISION TREE FOR SAFETY EVALUATION OF
NEW FOOD ADDITIVES
Timothy B. Adams, Scientific Director, The Flavor and Extract
Manufacturers Association
10:10 am
APPLICATION OF THE MARGIN-OF-EXPOSURE (MOE) APPROACH TO FOOD
ADDITIVES
Michael J. DiNovi, Chemist, US FDA, Center for Food Safety and Applied
Nutrition
10:45 am
REFRESHMENT BREAK
11:00 am
CHEMOINFORMATICS APPROACHES FOR TOXICOLOGY PREDICTIONS
Kevin P. Cross, Vice President of Product Engineering, Leadscope, Inc.
11:30 am
REGULATORY USE OF COMPUTATIONAL TOXICOLOGY TOOLS AND
DATABASES AT THE FDA, OFFICE OF FOOD ADDITIVE SAFETY
Kirk B. Arvidson, US FDA, Center for Food Safety and Applied Nutrition
39
WEDNESDAY
This activity is supported by an educational donation provided by:
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
SYMPOSIUM XVI
FDA-INDUSTRY DIALOGUE ON THE DRAFT GUIDANCE ON ASSESSMENT
OF A BUSE P OTENTIAL OF DRUGS
Frank Lloyd Wright I-J
Jennie Walgren, Eli Lilly and Company
David Compton, sanofi-aventis
SESSION CHAIRS:
Publication in early 2010 of the draft FDA guidance on assessment of abuse potential of drugs has sharpened
interest in the complexities of evaluating the abuse liability of new pharmaceuticals. The draft guidance is
comprehensive in its scope, covering the chemistry, manufacturing, animal behavior studies, clinical studies and
post-marketing experience that comprises assessment of abuse potential of a new drug. Understanding the
intricacies of this path has been the topic of discussion in various venues in the scientific community and in
November 2010 led to a day-and-a-half dialogue session between representatives of the pharmaceutical industry
and members of FDA's Controlled Substances Staff (CSS). This symposium will highlight important discussion
points of this scientific communication session and will explore key issues still open for debate. Topics for
discussion will include preclinical and clinical study designs, regulatory expectations, and a proposed flow chart
that synthesizes the draft guidance's recommendations for preclinical abuse liability assessments. The dialogue
session was a unique opportunity for industry and regulators to engage in open exploration of the intersection
between science and the regulation of evaluating new drugs for abuse potential.
9:00 am
SUMMARY OF ISSUES COVERED IN THE FDA-INDUSTRY 2010 DIALOGUE
SESSION ON THE DRAFT GUIDANCE ON ASSESSMENT OF ABUSE
POTENTIAL OF DRUGS
Jennie L. Walgren, Senior Research Scientist, Eli Lilly and Company
9:30 am
STUDY DESIGN OF ANIMAL BEHAVIOR STUDIES
Kristin Horn, Research Investigator II, Bristol-Myers Squibb
10:00 am
REFRESHMENT BREAK
10:20 am
CLINICAL STUDY DESIGN CONSIDERATIONS
Marta Sokolowska , Director, Center of Excellence for Abuse Liability,
Grünenthal USA, Inc.
10:50 am
REGULATORY EXPECTATIONS
Beatriz Rocha, Director, Merck & Co., Inc.
11:20 am
FLOW CHART HIGHLIGHTING KEY DECISION POINTS IN PRECLINICAL
PROGRESSION
Mary Jeanne Kallman, Director, Neuroscience, Covance Laboratories, Inc.
11:50 am
Q&A
40
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIUM XVII
ANIMAL WELFARE: WHERE SCIENCE MEETS ETHICS
Frank Lloyd Wright G-H
The session is intended to stimulate thinking, awareness, and understanding of the place where animal welfare
and changing regulatory guidelines connect to contemporary toxicology and pharmacology. Recent regulatory
directives in Europe and new laboratory animal care and use guidances in the USA are increasing the focus on
animal welfare considerations in our laboratories and research studies.
The speakers bring a variety of
perspectives to the forefront of consideration in planning and conducting modern toxicology and safety studies
while sharing their successes in achieving both scientific excellence and animal welfare goals.
This activity is supported by an educational donation provided by:
CHARLES RIVER
WELCOME AND INTRODUCTION
Steve Hachtman, Data Sciences International
Russette Lyons, Novartis Institutes for Biomedical Research
Russette Lyons, Head, Education Office, Novartis Institutes of Biomedical
Research
9:15 am
WHAT’S NEW IN ANIMAL WELFARE AND IN THE NEW GUIDE? WHERE DID
WE COME FROM, WHY ARE WE HERE AND WHERE ARE WE GOING?
Patricia V. Turner, Assoc. Prof. Dept. Pathobiology, Program Leader
Graduate Studies in Laboratory Animal Sciences, University of Guelph
9:50 am
SCIENCE, 3R’S AND EXPERIMENTAL DESIGN…. SHIFTING THE BALANCE
WITH NEW TECHNOLOGY AND BETTER EXPERIMENTAL DESIGNS TO
SUPPORT IMPROVED ANIMAL WELFARE
Henry Holzgrefe, Scientific Advisor, Navigator Services, Charles River
Laboratories
10:25 am
REFRESHMENT BREAK
10:45 am
DIRECTIVE 2010/63/EU: THE RENEWED EUROPEAN FOCUS ON
PROTECTION OF ANIMALS USED FOR SCIENTIFIC PURPOSES AND ITS
INFLUENCE ON OUR RESEARCH
Karen Blumer, Scientific Affairs/Global Animal Welfare Policies, Novartis
International AG
11:25 am
DEPARTMENTAL COOPERATION FOR BETTER SCIENCE AND BETTER
WELFARE: A CASE STUDY
Russell Bialecki, Associate Director of Safety Pharmacology, AstraZeneca
41
WEDNESDAY
SESSION CHAIRS:
9:00 am
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
AFTERNOON SYMPOSIUM
SYMPOSIUM XVIII
HOT TOPICS!
Frank Lloyd Wright F
The Hot Topics session will provide a variety of topics that include key updates to the International Conference on
Harmonization (ICH) Guidelines and FDA regulatory perspectives that serve as a guide to Pharmaceutical Safety
Evaluation. Presentations will be provided by members of the ICH working committee and other regulatory
professionals that have unique insights into the regulatory process. In addition, multiple late-breaking hot topics
will be included in the program as ~10-minute overviews of broad interest topics. Examples from last year include
discussion of “Recent FDA Facility Audit Citations – Impact Perspective and Collaborative Industry Responses,” and
“FDA Update - Pregnancy and Lactation Labeling Rule.” This session is critical for regulatory toxicologists in the
pharmaceutical industry as well as those that are impacted by evolving regulatory requirements which includes a
majority of ACT attendees including industry, CRO, and academic scientists.
This activity is supported by an educational donation provided by:
SCILUCENT, LLC
1:30 pm
INTRODUCTION
Drew Badger, Director of Global Regulatory Affairs, Amgen Inc.
CURRENT STATUS OF BIOSIMILAR LEGISLATION
Barbara J. Mounho, Amgen Inc.
PERSPECTIVES OF A PHARM/TOX REVIEWER IN THE PULMONARY,
ALLERGY, AND RHEUMATOLOGY PRODUCTS DIVISION
Molly (Shea) Topper, Pharmacology/Toxicology Supervisor, US FDA, CDER,
Division of Pulmonary, Allergy, and Rheumatology Products
Mary Ellen Cosenza, Amgen Inc.
Drew Badger, Amgen Inc.
SESSION CHAIRS:
3:00 pm
REFRESHMENT BREAK
ICH S6 UPDATE
Shawn M. Heidel, Director, Toxicology, Eli Lilly and Company
UPDATE ON ICH M7 GUIDANCE WITH EMPHASIS ON QSAR AND
GENOTOXIC IMPURITIES
Kenneth L. Hastings, Associate Vice President, Regulatory Policy, sanofiaventis
42
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
INSTRUCTIONS FOR PREPARING POSTERS
FOR THE ANNUAL MEETING OF THE
AMERICAN COLLEGE OF TOXICOLOGY
The Poster Session has been scheduled for Tuesday, November 8, 2011 from
5:30 pm until 7:00 pm. You have been assigned a number for the exact location
of your poster.
Micrographs, photomicrographs, charts, and graphs should be mounted on firm
mounting board. Matte finish on photographs gives the best visibility. Matte
surface paper may be used, or you can simply dry glossy prints with the emulsion
side of the paper facing away from the drying drum surface.
Presenters should provide their own push pins (5/8” long) for attaching posters to the display unit.
The Poster Boards will be available Sunday evening, November 6, 2011. Posters
should be set up by Monday morning to be available for as long as possible to
attendees.
You are expected to be present at your poster for discussion and to answer
questions during the 5:30 pm to 7:00 pm Poster Session, Tuesday, November 8,
2011.
Please remove your posters at the end of the session (7:00 pm) on Tuesday evening. ACT IS NOT RESPONSIBLE
FOR REMOVING OR STORING POSTERS.
43
WEDNESDAY
Each presentation is assigned a 4’ x 8’ cork board that includes 2.2. square
meters (24 square feet) on which to display data. Please identify your poster
with a title and the names of the investigators in 1” (2.5 cm) lettering at the top
of the display. It is very helpful to post a copy of your abstract.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIA AND CONTINUING EDUCATION COURSE
CHAIRS AND SPEAKERS
Timothy B. Adams, Ph.D.
Scientific Director
The Flavor & Extract Manufacturers Associate
1620 I Street, N.W.
Washington, D.C., 20006-4035
202.293.5800 202.463.8998
tadams@therobertsgroup.net
Cristian Tudorel Badea, Ph.D.
Associate Professor, Radiology
Duke University Medical School
Center for In Vivo Microscopy
Room 139, Bryan Research Building for
Neurobiology
Durham, NC 27710
919.684.7509
cristian.badea@duke.edu
Laura Andrews, PhD., DABT, Fellow ATS
Vice President, Pharmacology and Toxicology
Genzyme
5 Mountain Road
Framingham, MA 01701
508-271-3713 508-661-1854
laura.andrews@genzyme.com
Drew A. Badger, PhD, DABT
Director, Regulatory Affairs
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320
805.447.5875
dbadger@amgen.com
Kirk B. Arvidson, Ph.D.
Chemist
US FDA
CFSAN
Office of Food Additive Safety
HFS-275
College Park, MD 20770
301.436.1152 301.436.2965
kirk.arvidson@fda.hh.gov
Ted Baird, Ph.D.
Senior Director Safety Pharmacology &
Neurobehavioral Sciences
MPI Research
54943 North Main Street
Mattawan, MI 49071
269.377.5181 269.668.4151
ted.baird@mpiresearch.com
Carol S. Auletta, DABT, MBA, RAC
Director, Program Management
Huntingdon Life Sciences
P. O. Box 2360
Mettlers Road
East Millstone, NJ 08875-2360
732- 873-2550 x2960 732-873-3992
aulettac@princeton.huntingdon.com
Stephen A. Barat, Ph.D.
Director
Forest Research Institute
Harborside Financial Center
Plaza V
Jersey City, New Jersey 07311
201.437.8441 201.427.8993
stephen.barat@frx.com
Shana Azri-Meehan, Ph.D., DABT
Senior Principal Scientist
Forest Research Institute
Harborside Financial Center
Plaza V
Jersey City, New Jersey 07311
201.437.8451 201.427.8993
shana.azri-meehan@frx.com
Norman Barlow, DVM, PhD, MBA, MLD, DACVP,
DABT
Director
Sanofi
1041 Route 202-206
Mail Code: JR2-103A
Bridgewater, NJ 08807
908.231.2733 908.231.2629
norman.barlow@sanofi-aventis.com
44
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Steve Beck
Development Mgr., Non-clinical Sfty Projects
GlaxoSmithKline Research & Development
3F69
Park Road
Ware, Hertfordshire, SG12 0DO
England, UK
+44.1992.502124
steve.l.beck@gsk.com
2011
Russell Bialecki, PhD
Associate Director of Safety Pharmacology
Astra Zeneca
P. O. Box 1543
1800 Concord Pike
Wilmington, DE 19850-5437
302.886.5356 302.886.3889
russell.bialecki@astrazeneca.com
Karen Blumer, Ph.D.
Scientific Affairs/Global Animal Welfare
Policies
Novartis International AG
Forum 1
Novartis Campus
CH-4056 Basel
Switzerland
+41.61.3242675 +41.61.3242444
karin.blumer@novartis.com
William P. Beierschmitt, PhD, DABT
Associate Research Fellow
Pfizer Global R&D
Drug Safety Research & Development
Eastern Pt Rd., Bldg. 274
Groton, CT 06340
860.441.5245 860.441.5499
william.p.beierschmitt@pfizer.com
Lisa Beilke, PhD.
Research Scientist II
Gilead Sciences, Inc.
Safety Evaluation Department
333 Lakeside Drive
Foster City, CA
650.522.6361 650.522.5266
lisa.beilke@gilead.com
Brad Bolon
Associate Professor – Clinical
Department of Veterinary Biosciences
The Ohio State University
1900 Coffey Road – 350 VMAB
Columbus, OH 43210
614.292.0676 614.292.6473
brad.bolon@cvm.osu.edu
Peter J. Boogaard
Senior Toxicologist
Shell International bv
PO Box 162
2501 AN
The Hague, The Netherlands
+31 70 37 72 123 +31 70 37 72 840
peter.boogaard@shell.com
Cindy L. Berman, Ph.D.
Independent Consultant
15 Campbell Road
Wayland, MA 01778
508.358.4906 508.464.0487
cberman@alum.mit.edu
William J Brock, Ph.D., DABT, ATS
Principal
Brock Scientific Consulting
19909 Hamil Circle
Montgomery Village, MD 20886
301.519.3666 301.926.4792
billbrock@comcast.net
Brian R. Berridge, DVM, Ph.D.
Director, Regulatory & Discovery Pathology
GlaxoSmithKline Safety Assessment
5 Moore Dr., RD9.3005
Research Triangle Park, NC 27709
919.315.6592
brian.x.berridge@gsk.com
Alan P. Brown, Ph.D., DABT
Senior Toxicology Consultant
Integrated Nonclinical Development Solutions Inc.
3005 Miller Avenue
Ann Arbor, MI 48103
734.929.5392 734.929.5393
alan.brown@inds-inc.com
45
SPEAKERS
R. Daniel Benz, Ph.D.
Computational Toxicologist
US FDA, CDER
Office of Testing and Research
2012 W064
10903 New Hampshire Avenue
Silver Spring, MD 20993
301.796.1645 301.796.9818
r.daniel.benz@fda.hhs.gov
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Florence G. Burleson, Ph.D.
Executive Vice President
BRT – Burleson Research Technologies, Inc.
120 First Flight Lane
Morrisville, NC 27560
919.719.2500 919.719.2505
fburleson@brt-labs.com
Laura A Conour, DVM, DACLAM
Director, Research Resources
Princeton University
Office of the Dean of Research
91 Prospect Avenue
Princeton, NJ 08540
609.258.7857 609.955.1459
lconour@princeton.edu
Gary R. Burleson, Ph.D.
President
BRT – Burleson Research Technologies, Inc.
120 First Flight Lane
Morrisville, NC 27560
919.719.2500 919.719.2505
gburleson@brt-labs.com
Mary Ellen Cosenza, Ph.D., DABT
Emerging Markets International Regulatory
Affairs and Safety Regulatory Affairs
Amgen Inc.
One Amgen Center Drive
38-4-C
Thousand Oaks, CA 91320
805.447.6318 805.499.9228
mcosenza@amgen.com
Joseph W. Carraway, DVM, M.S.
Director, Toxicology
NAMSA
6750 Wales Road
Northwood OH 43619-1012
419.662.4440 419.666.2954
Kevin P. Cross
Vice President of Product Engineering
Leadscope, Inc.
1393 Dublin Road
Columbus, OH 43215
kcross@leadscope.com
Charles R. Clark
Principal Toxicology Consultant
ConocoPhillips Company
1204 Phillips Building
Bartlesville, OK 74004
918.661.9469
c.r.clark@conocophillips.com
Jon Daniels, Ph.D., DABT, ERT
Executive Vice President/ Senior Toxicologist
Intrinsik Health Sciences, Inc.
6605 Hurontario Street, Suite 500
Mississauga, Ontario L5T 0A3
Canada
905.364.7816
jdaniels@intrinsik.com
Robert W. Coatney, DVM, Ph.D.
Director, Comparative Biology and Medicine
GlaxoSmithKline
P.O. Box 1539, UW2630
King Of Prussia, PA 19406
610.270.4523 610.270.5630
robert.w.coatney@gsk.com
John P. Devine, DABT
General Manager
BASi
10424 Middle Mount Vernon Road
Mount Vernon, IN 47620
812-985-3400 (X 102)
jdevine@basinc.com
David Compton, PhD, DABT
Principal Research Investigator
sanofi-aventis
1041 Route 202-206, PO Box 6800
Mail code: JR2-103A
Bridgewater NJ 08807-0800
908.541.5328 908.231.2629
david.compton@sanofi-aventis.com
Michael J. DiNovi, Ph.D.
Chemist
US FDA
CFSAN
HFS-255
Riverdale, MD 20770
301.436.1320 301.436.2964
michael.dinovi@fda.hha.gov
46
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
John Dooley, Ph.D.
Senior Research Fellow, Preclinical R&D
Codman & Shurtleff, Inc.
(Division of Johnson & Johnson)
Welsh & McKean Roads
P. O. Box 776
Spring House, PA 19477-0776
215.628.5315 215.540.4925
jdooley2@its.jnj.com
Dr Andrew Feilden CSci CChem MRSC
Principal Consultant
Smithers Rapra
Shrewsbury
Shropshire, SY4 4NR
United Kingdom
+44 (0)1939 250383
Direct Dial +44 (0)1939 252418
afeilden@rapra.net
Robert T. Dorsam, Ph.D.
Pharmacologist
US FDA
Divsion of Drug Oncology Products
10903 New Hampshire Avenue
WO Bldg., Rm. 2366
Silver Spring, MD 20993
301.796.1623
robert.dorsam@fda.hhs.gov
Susan P. Felter, Ph.D.
Procter & Gamble Company
Miami Valley Innovation Center
P. O. Box 538707
Cincinnati, OH 45253-8707
513.627.1958 513.386.1504
felter.sp@pg.com
Holly Dursema, MS, DABT
Senior Principle Scientist
Boehringer Ingelheim Pharma, Inc.
900 Rodgebury Road
Ridgefield, CT 06877
203.798.5694
holly.dursem@boehringer-ingelheim.com
Nicolay Ferrari, Ph.D.
Director Pharmacology
Topigen Pharmaceuticals part of Pharmaxis Ltd
Grp
2901 Rachel Street East, Suite 13
Montreal, QB, H1W 4A4
Canada
514.868.0077 x239 514.868.0011
nicolay.ferrari@topigen.com
Kimberly D. Ehman, Ph.D., DABT
Senior Toxicologist, Program Manager
Toxicology Regulatory Services
2365 Hunters Way
Charlottesville, VA 22911
434.977.5957 434.977.0899
kehman@toxregserv.com
Oliver Flint, Ph.D.
Research Fellow
Bristol-Myers Squibb
P. O. Box 5400
Princeton, NJ 08543
609.8184504
oliver.flint@bmc.com
Amy Ellis, Ph.D.
Pharm/Tox Reviewer
US FDA
CDER, OND
10903 New Hampshire Avenue
Silver Springs, MD 20993
301.796.1400 301.796.9882
amy.ellis@fda.hhs.gov
James J. Freeman, Ph.D., DABT
Distinguished Toxicology Associate
ExxonMobil Biomedical Sciences, Inc. (EMBSI)
1545 Route 22 East
Annandale NJ 08801
908-730-1123 908-730-1199
james.j.freeman@exxonmobil.com
Shayne C. Gad, Ph.D., DABT, ATS
Principal
Gad Consulting Services
102 Woodtrail Lane
Cary, NC 27518
919.233.2926 919.233.2927
scgad@ix.netcom.com
Nancy Everds, DVM, DACVP
Clinical Pathologist
Amgen Inc.
1201 Amgen Court West
Seattle, WA 98119
206.265.8334 206.599.6460
neverds@amgen.com
47
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Alema Galijatovic-Idrizbegovic, Ph.D.
Associate Director
Merck & Co., Inc.
Dept. of Safety Assessment
770 Sumneytown Pike, WP45-201
West Point, PA 19486
215.872.8929
alema_galijatociv@merck.com
Nigel Greene Ph.D.
Associate Research Fellow
Pfizer Inc.
Compound Safety Prediction Group
Worldwide Medicinal Chemistry
MS 8118-B3
Eastern Point Road
Groton, CT 06340
860.715.4921 860.686.7011
nigel.greene@pfizer.com
Prof. Dr. Paul-Georg Germann, DVM, MSC
Toxicol, DECVP, Fellow IATP
Sr. Vice President, Discovery to Preclin Dvlpmnt
Nycomed GmbH
Byk-Gulden-Str.2
Konstanz, 78467
Germany
0049.151.18056573 0049.7531.849410
paul-georg.germann@nycomed.com
Markus Grompe, M.D
Director, Oregon Stem Cell Center
Founder and Chief Scientific Officer
Yecuris Corporation
Oregon Health & Science University
3181 SW Sam Jackson Park Road
Portland, OR 97239
503.494.6888 503.418.5044
grompem@ohsu.edu
Hanan Ghantous, Ph.D., DABT
Supervisory Toxicologist
US FDA, CDER, OND, OAP
10903 New Hampshire Ave
CDER/OND/OAP/Div. of Antiviral Products
Silver Spring, MD 20903
301.796.1500 301.796.9883
hanan.ghantous@fda.hhs.gov
Robert J. Guttendorf, RPh, Ph.D.
Sr. Consultant, DMPK
Aclairo Pharma Development Group, Inc.
1950 Old Gallows Rd., Suite 300
Vienna, VA 22182
703.506.6760, Ext 316 703.506.0142
rguttendorf@aclairo.com
Gary A. Gintant, Ph.D.
Research Fellow
Chairman, Abbott QT Working Group
Global Pharmaceutical R&D
Abbott
100 Abbott Park Rd
Abbott Park , IL 60048-6119
847.935.1688
gary.gintant@aboott.com
Robin Guy, MS, DABT
Robin Guy Consulting, LLC
P.O. Box 830
Lake Forest, IL 60045
847.295.9250 847.295.8251
rcg@robingury.com
Steve Hachtman, MA
Director of Applications Development
DSI
119 14th Street NW
St Paul, MN 55112
651-481-7426
shachtman@datasci.com
Warren E. Glaab, Ph.D.
Safety Assessment
Merck and Co.
770 Sumneytown Pike-WP45-320
West Point, PA 19486-0004
215.652.8398 215.652.4944
warren_glaab@merck.com
Robert Hall, DVM, Ph.D., DACVP
Clinical Pathologist
Covance Laboratories Inc.
3301 Kinsman Blvd.
Madison, WI 53704
608.242.2712 ext. 2326
robert.hall@covance.com
Thomas Gray
Senior Scientific Advisor
American Petroleum Institute
1220 L Street, N.W.
Washington, DC
202.682.8480 202.682.8270
grayt@api.org
48
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Robert L. Hamlin, Ph.D., DVM
Professor Veterinary Med, Prof. Biomed Eng.
Ohio State University
480 VMAB
1900 Coffey Road
Columbus, OH
614.292.8122 614.292.6473
hamlin.1@osu.edu
Melanie Hartsough, Ph.D.
Senior Consultant
Biologics Consulting Group, Inc.
400 N. Washington Street, Suite 100
Alexandria, VA 22314
301.742.3665 703.548.7457
mhartsough@bcg-usa.com
Jeff A. Handler, Ph.D., MBA, DABT
President
JAH Associates, LLC
651 Crestwood Road
Wayne, PA 19087
610.716.1848 610.971.0446
jeff@feehandlerconsulting.com
Catrin Hasselgren
Prinicipal Scientist
AstraZeneca R&D
Global Safety Assessment
Pepparedsleden 1
MoIndal, Sweden
+46 (0) 31 7064283 +46 (0) 727207180
catrin.hasselgren@astrazeneca.com
Jerry F. Hardisty, DVM, DACVP, Fellow IATP
CEO/Veterinary Pathologist
EPL, Inc.
P.O.Box 12766
Research Triangle Park, NC 27709
919.998.9407 919.998.9607
jhardisty@epl-inc.com
Craig R. Hassler PhD
Manager of Safety Pharmacology
Battelle Memorial Institute
505 King Ave.
Columbus OH 43206
614.424.7623
hasslerc@battelle.org
Patricia P. Harlow, Ph.D.
Pharmacologist
US FDA
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
301.796.5318 301.796.9841
patricia.harlow@fda.hhs.gov
Kenneth L. Hastings, DrPH, DABT, ATS
Associate VP, Regulatory Policy
sanofi-aventis
Corporate Reg Affairs Office
4520 East West Highway, #210
Bethesda, MD 20814
301. 771.4267 301.771.4287
kenneth.hastings@sanofi-aventis.com
Alison Harrill, Ph.D.
Hamner Center for Drug Safety Sciences
The Hamner Institutes for Health Sciences
6 Davis Drive
P.O. Box 12137
Research Triangle Park, North Carolina 27709
919.558.1200 919.558.1400
aharrill@thehamner.org
Shawn M. Heidel, DVM, PhD
Director, Toxicology
Eli Lilly and Company
Lilly Corporate Center, DC1940
Indianapolis, IN 46285
317.433.5876 317.651.5859
sheidel@lilly.com
Wafa A. Harrouk, M.Sc., Ph.D.
Senior Pharmacology/Toxicology Reviewer
US FDA, CDER, OND, ODEIV
10903 New Hampshire Avenue
Silver Spring, MD 20993
301.796.0908 301.796.9899
wafa.harrouk@fda.hhs.gov
Scott P. Henry, Ph.D.
ISIS Pharmaceuticals
2292 Faraday Avenue
Carlsbad, CA 92008
760.603.3813 760.603.3862
sherry@isisph.com
49
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
David W. Hobson, Ph.D., DABT
President
LoneStar Pharm Tox LLC
613 Pleasant Valley Drive
Boerne, TX 78006
210.269.6169 830.229.5782
dave@lonestarpharmtox.com
2011
Jeff Jamison
Ophthy-DS, Inc. and MPI Research
54943 N. Main Street
Mattawan, MI 49071
269.250.2177 480.247.4464
jeff.jamison@ophthy-ds.com
Dr. Henry Holzgrefe
Scientific Advisor, Navigator Services
Charles River Laboratories
6995 Longley Lane
Reno, NV 89511
775.682.2249
henry.holzgrefe@crl.com
G. Allan Johnson, Ph.D.
Charles E. Putman Professor of Radiology,
Physics, and Biomedical Engineering
Duke University Medical Center
Center for In Vivo Microscopy
Room 139, Bryan Res Bldg. for Neurobiology
Durham, NC 27710
919.684.7758
gjohnson@duke.edu
Kristin Horn, Ph.D.
Research Investigator II
Bristol-Myers Squibb
4601 Hwy 62 East
Building 101
P.O. Box 1500
Mt. Vernon, Indiana 47620
812.307.2196 812.307.2383
kristin.horn@bms.com
Mary Jeanne Kallman, Ph.D.
Director, Neuroscience
Covance Laboratories, Inc.
671 S. Meridian
Greenfield, IN 46140-5006
317.467.2428 317.277.6770
mary.kallman@covance.com
Thomas T. Kawabata, Ph.D.
Pfizer, Inc.
MS 8274-1206
Groton, CT 06340
860.441.0527
thomas.t.kawabata@pfizer.com
Kristina Howard, D.V.M., Ph.D.
Commissioner’s Fellow
U.S. Food and Drug Administration
N29B RM4G13
9000 Rockville Pike
Bethesda, MD 20893
kristina.howard@fda.hhs.gov
Norman Kim, M.S., DABT
Director, Pharmacotoxicology
Biogen Idec, Inc.
14 Cambridge Center
Cambridge, MA 02142
617.679.4995
norman.kim@biogenidec.com
Timothy Hummer
Pharmacology/Toxicology Reviewer
US FDA
CDER
10903 New Hampshire Avenue
White Oak Bldg. 22, Rm. 3109
Silver Spring, MD 20933
301.796.0326
tim.hummer@fda.hhs.gov
Fred Kirchner, Ph.D.
Executive Director, Toxicology, Pathology, Safety
Pharmacology
Covance Labs.
3301 Kinsman Boulevard
Madison, WI 53532
608 241-7409
fred.kirchner@covance.com
Laurie Iciek, PhD
Principal Toxicologist
MedImmune
Biologics Safety Assessment; Translational
Science
One MedImmune Way
Gaithersburg, MD 20878
301.398.4793 301.398.9793
iciekl@medimmune.com
50
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Doug Kornbrust, Ph.D., DABT
President
Preclinsight
7245 Lingfield Drive
Reno, NV 89502
775.857.4113 775.857.2912
preclinsight@charter.net
Kathy Lee, Ph.D.
Lead Interdisciplinary Scientist
US FDA-CDER
900 Rockville Pike
N29A, Rm. 2D16
Bethesda, MD 20892
301.594.6679
kathy.lee@fda.hhs.gov
Joseph Krueger, Ph.D.
Director of Biology
Flagship Biosciences
5 Ivy Lane
Andover, MA 01810
720.412.8625
jkrueger@flagshipbio.com
Patrice Lee
Senior Director of Pharma and Toxicology
Array BioPharma, Inc.
3200 Walnut Street
Boulder, CO 80301
303.386.1482 303.381.6652
patrice.lee@arraybiopharma.com
Periannan Kupasami, Ph.D.
Professor
The Ohio State University College of Medicine
420 W 12th Ave.
Columbus OH 43210
614.292.8998
kuppusamy.1@osu.edu
Serguei Liachenko
Director, Bio-Imaging
US FDA, NCTR
NCTR/OCS/NCTR/DDR/DNT
Mail stop HFT-132
3900 NCTR Road
Jefferson AR 72079
870.543.7203 870.543.7745
serguei.liachenko@fda.hhs.gov
Pierre Lainee
Principle Scientist R & D
Astra Zeneca, UK
Macclesfield
England, United Kingdom
+44.1625.232.335
pierre.lainee@astrazeneca.com
Gordon R. Loewen, Ph.D.
Sr. Dir., Drug Metabolism & Pharmacokinetics
Infinity Pharmaceuticals
780 Memorial Dr.
Cambridge, MA 02139
617.453.1341 617.453.1001
gordon.loewen@infi.com
Richard W. Lane, Ph.D., DABT
Scientific & Regulatory Affairs
PepsiCo
350 Columbus Avenue
Valhalla, NY 10595
914.742.4538 914.749.3356
richard.lane@pepsico.com
Russette M. Lyons, PhD
Head, Education Office
Novartis Institutes for BioMedical Research
250 Massachusetts Avenue
607/931F
Cambridge, MA 02139
617. 871.3112
russette.lyons@novartis.com
Donna Lee, PhD, DABT
Associate Scientist, Safety Assessment
Genentech
1 DNA Way
South San Francisco, CA 94080
650-467-4587
lee.donnaw@gene.com
Peter C. Mann, DVM, DACVP
Manager, EPL NorthWest
EPL, Inc.
2544 13th Avenue, W
Seattle, WA 98119
206.284.1900 206.284.1901
pmann@epl-inc.com
51
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Kevin S. McDorman, DVM, PhD, DACVP
General Manager
Charles River Pathology Associates
15 Worman's Mill Court
Frederick, MD 21701
301.624.2918 301.694.8868
kevin.mcdorman@crl.com
Vincent A. Murphy, Ph.D., DABT
Principal Research Investigator
Array BioPharma, Inc.
3200 Walnut Street
Boulder, CO 80301
303.386.1343 303.381.6652
vincent.murphy@arraybiopharma.com
Timothy J. McGovern, Ph.D.
Nonclincal/Regulatory Consultant
SciLucent LLC
585 Grove Street
Suite 300
Herndon, VA 20170
703.435.0333 x242 703.435.0440
t.mcgovern@scilucent.com
James Murray
Staff Scientist, Toxicology
Genzyme
5 Mountain Road
Framingham MA 01701
508-271-2837
james.murray@genzyme.com
Kathy McGown
Director, Knowledge Resources
FoxKiser
750 17th St NW, Suite 1100
Washington, DC 20006
202.778.2358
kmcgown@foxkiser.com
L. Peyton Myers, Ph.D.
Pharmacology/Toxicology Reviewer
US FDA, CDER/OND/OAP
Div. of Antiviral Products
10903 New Hampshire Ave
Silver Spring, MD 20903
301.796.2217 301.796.9883
laine.myers@fda.hhs.gov
Richard H. McKee
Distinguished Toxicology Associate
ExxonMobil Biomedical Sciences, Inc.
1545 Route 22 East
Annandale, NJ 08801-3059
908.730.1037 908.730.1199
richard.h.mckee@exxonmobil.com
Mark Nicolich, Ph.D.
Statistician
Cogimet
24 Lakeview Road
Lambertville, NJ 08530
609.397.4089
mark.nicolich@gmail.com
Susan McPherson, MSc
Executive Director Toxicology
WuxiAppTec
1318 Wuzhong Avenue
Wuzhong District
Suzhou, China
86 512 6650 9570 86 512 6883 7303
sue@candsmcpherson.com
Mark Niehoff
Study Director Toxicology
Covance Laboratories
Kesselfeld 29
Munster, DE D-48163
Germany
+49.251.9798.149
marc.niehoff@covance.com
Barbara J. Mounho, PhD, DABT
Director, Global Regulatory Affairs Biosimilar
Policy and Strategy
Amgen Inc.
One Amgen Center Drive
17-1-C
Thousand Oaks, CA 91320-1799
805.447.5619 805.498.2481
bmounho@amgen.com
Todd Palmby, Ph.D.
Pharmacology/Toxicology Reviewer
US FDA
CDER
10903 New Hampshire Avenue
W022-5205
Silver Spring, MD 20993-0002
todd.palmby@fda.hhs.gov
52
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Richard S. Paules, Ph.D.
Acting Chief, Lab of Toxicology & Pharma
Head, Environmental Stress and Cancer Group
Director, NIEHS Microarray Core Facility
NIEHS, NIH
111 Alexander Drive, Room D266B
P.O. Box 12233, Mail Drop D2-03
Research Triangle Park, NC 27709-2233
919.541.3710 919.316.4771
paules@niehs.nih.gov
William T. Reinholt
Manager, Quality Assurance
MPI Research, Inc.
54943 North Main Street
Mattawan, MI 49071-9399
269.668.3336 x1624
william.reinholt@mpiresearch.com
James Render, DVM, PhD, DACVP
Veterinary Pathologist
NAMSA
6750 Wales Road
Northwood, OH 43619
419.662.4451 419.662.4802
jrender@namsa.com
Syril Pettit, MEM
HESI Associate Director
HESI
1156 15th St NW
Washington DC 20005
202.659.3306 202.659.3617
spettit@ilsi.org
M. Stacey Ricci, Sc.D.
Senior Toxicologist
US FDA
10903 New Hampshire Avenue
HFD-107
Silver Spring, MD, 20993
301-796-1770
stacey.ricci@fda.hhs.gov
Mark W. Powley, Ph.D.
Pharmacologist
U.S. Food and Drug Administration
Division of Antiviral Products
W022 RM 6373
10903 New Hampshire Avenue
Silver Spring, MD 20993
301.796.5079
mark.powley@fda.hhs.gov
Richard E. Ridgewell, Ph.D.,
Associate Director, Drug Metabolism
Covance Laboratories Inc.
3301 Kinsman Boulevard-02
Madison, MI 53704
608.310.8225 608.241.7412
richard.ridgewell@covance.com
Lynnda Reid, Ph.D.
Supervisory Pharmacologist
US FDA, CDER
Division of Reproductive & Urologic Products
10903 New Hampshire Avenue
White Oak Bldg. 22, Rm. 5388
Silver Spring, MD 20993
301.796.0984 301.796.9897
lynnda.reid@fda.hhs.gov
Maria I. Rivera
Pharmacologist/Toxicologist
US FDA
CDER
10903 New Hampshire Avenue
Bldg. 22
Silver Spring, MD20993
301.796.0796 301.796.9881
maria.rivera@fda.hhs.gov
Melissa Reinert
Senior Quality Assurance Auditor
Biotechnical Services, Inc.
4610 West Commercial Drive
North Little Rock, AR 72116
501.758.6290 x116 501.753.5963
mreinert@biotechnicalservices.com
Beatriz Rocha
Director
Merck & Co., Inc.
126 E. Lincoln Ave
Rahway, NJ 07065-0900
732.594.3804 732.594.3235
beatriz_rocha@merck.com
53
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Brian M. Roche, PhD
Associate Manager Safety Pharmacology
Battelle Memorial Institute
505 King Ave.
Columbus OH 43206
614.424.7134
rocheb@battelle.org
Hilary Sheevers, Ph.D.
President, CEO
Aclairo PDG, Inc.
1950 Old Gallows Rd., Suite 300
Vienna, VA 22182
703.506.6760 X307 703.506.0142
hsheevers@aclairo.com
Paul L. Roney, Ph.D., DABT
Senior Consultant, Toxicology
INC Research
7361 Calhoun Place, Suite 500
Rockville, MD 20855
301. 296.1363 301.-838.3182
paul.roney@incresearch.com
Michael Shelton
Technical Director
Exova Inc.
9240 Santa Fe Springs Road
Santa Fe Springs, CA 90670-2618
562.948.2225 x602
mike.shelton@exova.com
Tom Rosol
Ohio State University
1925 Coffey Road
Columbus, Ohio 43210
614.292.5661 614.292.6473
rosol.1@osu.edu
Paul W. Snyder, DVM, Ph.D.
Professor of Pathology
Purdue University
725 Harrison Street
West Lafayette, IN 47907
765.494.9676 765.494.9830
snyderp@purdue.edu
Philip Sager, M.D., FACC, FAHA
Chair, Scientific Program Committee, Cardiac
Safety Research Consortium &
Pharmaceutical/Device Consultant
719 Carolina St.
San Francisco CA 94107
650.450.7477
psager@alum.mit.edu
Steve M. Snyder, MS
President
Outsourcing Support Services, Inc.
1148 Leesburg Drive
Leland, NC 28451
317. 408.0286 317. 770.7750
info@outsource-support.com
Nico Scheer, Ph.D.
Head of ADMET R&D
TaconicArtemis GmbH
Neurater Ring 1
Cologne, 51063
Germany
+49.221.9645343 +49.221.9645321
nico.scheer@taconicartemis.com
Marta Sokolowska , Ph.D.
Director, Cntr of Excellence for Abuse Liability
Grünenthal USA, Inc.
One Pluckemin Way
Bedminster, NJ 07921
908.306.0024 908.306.1631
marta.sokolowska@grunenthal.com
Richard C. J. Somerville, Ph.D.
Distinguished Professor Emeritus & Research
Professor
Scripps Institution of Oceanography
University of California San Diego
9500 Gilman Drive, Dept. 0224
La Jolla, CA 92093-0224
858.534.4644 858.534.8561
rsomerville@ucsd.edu
Capt. Mark Seaton, USPHS
Regulatory Review Officer
US FDA
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
301.796.3408 301.796.9883
mark.seaton@fda.hhs.gov
54
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Christopher J. Somps
Pfizer
Eastern Point Road
Groton, CT
860.715.2841 860.732.7049
christopher.j.somps@pfizer.com
Dr. O. Joseph Trask, Jr.
Head, Cellular Imaging Core
The Hamner Institutes for Health Sciences
6 Davis Drive
Research Triangle Park, NC 27709
919.558.1292
jtrack@thehamner.org
Ron Steigerwalt, Ph.D., DABT
Preclinical Director
Amgen Inc.
One Amgen Center Drive
MS: 29-2A
Thousand Oaks, CA 91320
805.313.5210
rsteiger@amgen.com
Mingyi Trimble, ScD, DABT
Study Director
Covance Laboratories Inc.
2701 E. Ryan Rd.
Chandler AZ 85286
480.384.3637 480.927.3912
mingyi.trimble@covance.com
Jacqueline Tarrant, BVSc, PhD, DACVP
Scientist - Pathologist
Genentech
1 DNA way
South San Francisco, CA 94080
650.467.7420
tarrant.jacqueline@gene.com
Niraj Tripathi, BVSc, MVSc, PhD, DACVP
Clinical Pathologist
Covance Laboratories Inc.
3301 Kinsman Blvd.
Madison, WI 53704
608.242.2712 ext. 2562
niraj.tripathi@covance.com
Marque Todd, DVM MS DABT
Regulatory Strategy Lead
Pfizer, Inc.
10646 Science Center Drive
San Diego, CA 92121
858-526-4700
marque.todd@pfizer.com
Patricia V. Turner, BSc, MSc, DVM, DVSc,
DACLAM, DABT
Assoc. Prof. Dept. Pathobiology
Program Leader
Graduate Studies in Laboratory Animal Science
University of Guelph
Guelph, ON N1G 2W1
Canada
519.824.4120 x54497
pvturner@uguelph.ca
Molly (Shea) Topper
Pharmacology/Toxicology Supervisor
US FDA, CDER
Division of Pulmonary, Allergy, and
Rheumatology Products
CDER-White Oak, Bld.22, Rm 3242
10903 New Hampshire Avenue
Silver Spring, MD 20993
301.796.1291 301.796.9728
molly.shea@fda.hhs.gov
CT Viswanathan, Ph.D.
CT Viswanathan & Associates Inc.
240.423.4333
vishct@gmail.com
Jennie L. Walgren, Ph.D.
Senior Research Scientist
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285
317.433.0834 317.277.7601
walgrenje@lilly.com
Vince Torti, Ph.D., DABT
Pfizer
1077 Science Drive
La Jolla, CA 92121
858.622.3055
vince.torti@pfizer.com
55
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Mark D. Walker, DVM
Toxicologist
Frontier BioSciences, Inc.
20251 Century Blvd., Suite 325
Germantown, MD 20874
775.750.9021
mwalker@frontierbsi.com
Clynn Wilker, Ph.D., DABT
Ardea Biosciences
4939 Directory Place
San Diego, CA 92121
858.652.6678
cwilker@ardeabio.com
Dr. Jackie Williams
President-Elect, Radiation Research Society
Research Professor, Dept. Radiation Oncology
James P. Wilmot Cancer Center
Univ Rochester School of Medicine & Dentistry
601 Elmwood Avenue
Box 647
Rochester, NY 14642
585.275.1687 585.275.1531
jackie_williams@urmc.rochester.edu
Rob Wallis
Exec. Director, Head of Centres of Emphasis
Pfizer
Drug Safety Research & Development
Eastern Point Road
Groton, CT 06340
860.715.6644
rob.wallis@pfizer.com
Klaus Weber, Ph.D., DVM, MS
Toxicologic Pathologist
Harlan Laboratories, Inc.
Zelgliweg 1
Itingen, 4452
Switzerland
+41.61.975.1268 +41.61.875.1887
kweber@harlan.com
G. David Young, DVM, DACVP, DABT
President and Chief Pathologist
Flagship Biosciences, LLC
4683 Lee Hill Drive
Boulder, CO 80302
303.817.7886 303.444.0673
dave@flagshipbio.com
56
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
ABSTRACTS
Plenary Lectures
Monday
GLP MODERNIZATION: WHAT DOES THIS MEAN TO YOU CT
Viswanathan, Ph.D., CT Viswanathan & Associates Inc.
Nonclinical data generated in the early stages of
drug development are significant and form the basis of
understanding for possible safety concerns of the drug
candidate. This information is often critical in allowing
the clinical trials in humans to proceed. Current GLP
regulations provide a framework to conduct nonclinical
studies in a satisfactory manner. Optimization of these
regulations will provide further opportunities to
effectively collect robust and quality data. This
presentation will discuss the need for modernization,
the issues that need to be resolved, the outdated
practices that need to be eliminated and ways for
possibly reducing the regulatory burden. The ways in
which your future work can be affected and the
ongoing review of the comments for ANPRM
(advanced notice for proposed rule making) will be
discussed. The desirable future direction can be
enabled by collaborative efforts from Industry and the
Regulatory Agency.
rapidly within the next five to ten years, reaching nearzero well within this century. Conveying the scientific
rationale for urgent action is a critical communications
challenge, and the nature of the climate that we leave
to our children and grandchildren depends on it.
Wednesday
FALLOUT FROM FALLOUT: RISKS VERSUS HYPE
Jacqueline P. Williams, Ph.D., Research Professor,
University of Rochester School of Medicine &
Dentistry, Department of Radiation Oncology,
Rochester, New York.
This talk will provide a brief overview of the acute
effects of radiation, but will focus more on the delayed
outcomes from short-term and long-term exposure to
irradiation, drawing on our understanding from such
events as the Japanese A-bombs and Chernobyl, and
applying such findings to the recent incident at the
reactor site in Fukushima. Although relatively large
databases are available from these accidents and
incidents as well as the therapeutic field, our true
understanding of the biological mechanisms and
pathways that underlie the development of radiationinduced late effects still remains somewhat
hypothetical. Some of the main theories currently
being considered will be discussed, together with
suggestions for the likely strategies that may be used
to mitigate such outcomes.
PLENARY
ABSTRACTS
Tuesday
CLIMATE CHANGE AND SPEAKING TRUTH TO POWER:
HOW SOUND SCIENCE CAN INFORM WISE POLICY
Richard C. J. Somerville, Ph.D., Distinguished Professor
Emeritus & Research Professor, Scripps Institution of
Oceanography, University of California San Diego.
Man-made climate change is already occurring. The
science is compelling. Recent research findings include
measurements showing the Greenland and Antarctic
ice-sheets are losing mass and contributing to
accelerate sea level rise. Global sea level increases may
well exceed 1 meter (about 3 feet) by 2100, with a rise
of up to 2 meters (6 feet) considered possible. In
addition, Arctic sea ice has recently melted far beyond
the predictions of climate models. Patterns of
precipitation and weather extremes such as floods and
droughts are also changing. Yet, mankind continues to
emit gases that amplify the greenhouse effect. Recent
annual carbon dioxide emissions from fossil fuels were
about 40% higher than those in 1990. At today’s
emissions rates, after only 20 more years, the world
will no longer have a reasonable chance of limiting
global warming to less than levels widely considered to
be dangerous. To avoid severe climate disruption,
global emissions must peak and then start to decline
57
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
SYMPOSIA ABSTRACTS
Ia
BASIC TESTING REQUIREMENTS: ISO AND FDA
Joseph W. Carraway, DVM, MS, Director of Toxicology,
NAMSA, Northwood, OH
Medical device manufacturers want to get their
devices onto the market as soon as possible. However,
they are often confused about the preclinical testing
requirements necessary for submission to the US FDA
as well as countries outside the US. This session will
provide an overview of the testing preclinical tests
requirements for medical devices based on the ISO
10993 - Biological evaluation of medical devices. Part
1 of ISO 10993 will be reviewed and how a device’s
testing requirements are based on the devices tissue
contact and contact duration. In addition, some of the
unique requirements for the US and other countries
will be discussed.
that utilize nanotechnology now include a wide array
of device types and applications. Nanoparticles have
been widely used as antimicrobial agents in bandages
and surface coatings, they are increasingly being used
to enable in vitro diagnostic devices and various types
of nanoparticulate coatings are used to enhance
biocompatibility of implanted devices. Because
nanoparticulate dimensions create tremendous
surface area for both chemical and physical biologic
interactions and exist within the dimension between
enzymes and cellular structures, there is little wonder
that the use of nanotechnology in medical devices
results in concern for safety assessment. Because
nanotechnology is rapidly advancing and continuously
creating new and more elaborate and complex forms,
case by case assessment of safety has become the
most rational approach because safety assessment
procedures that were developed primarily to evaluate
the effects of chemicals often cannot be used without
at
least
some
modification
to
evaluate
nanotechnologies. Characterization and expression of
dose and exposure for nanomaterials can be
challenging. Current approaches and procedures for
safety assessment of medical devices that incorporate
nanotechnology will be presented along with an
examination of the nature of the driving forces that are
increasingly demanding completion of such
assessments prior to their medical use
Ib
ANALYTICAL APPROACHES FOR DEGRADATION
PRODUCTS, EXTRACTABLES AND LEACHABLES FROM
MEDICAL DEVICES
Michael Shelton, Technical
Director, Exova, Inc., Santa Fe Springs, CA
This presentation will provide an overview of the
types of analytical testing which can be used to
characterize extractable and leachable compounds
from medical devices. These compounds may include
artifacts from the raw materials (e.g., plasticizers, antioxidants, residual monomers), residues from
manufacturing (residual solvents from adhesives, mold
release agents, sterilant residues) or postmanufacturing (oxidation or other degradation
products).
It will include approaches for initial identification of
potential leachables, development of appropriate
leachate conditions, depending on the intended use of
the device, and analytical methods for the
measurement of leachables in finished products.
We will consider USP, EP, ISO and FDA methods and
guidances, and how they are applied to different types
of devices.
Id
Biocompatability Assessment of Antimicrobial
Devices
Shayne C Gad, Principal, Gad Consulting
Services
The assessment of biologic safety of a medical
device treated to avoid or minimize the risks of
infection requires assessment of two potential sources
of risk (device and antimicrobial actives) yet such
assessment needs to be performed in a manner which
avoids duplication effort or unnecessary testing, yet
assures safety and regulatory compliance.
The case of forms of indwelling catheter for long
term dialysis will be used as an example to illustrate
considerations, challenges and their solutions.
Ic
NANOTECHNOLOGY ENABLED DEVICE DESIGN AND
SAFETY ASSESSMENT.
David W. Hobson, Ph.D.,
DABT., LoneStar PharmTox LLC, Boerne, Texas.
The technologic ability to manipulate matter at the
atomic and nanometer scale reliably enough to
produce useful medical devices has been applied for
nearly two decades. Beginning with various
applications of simple nanoparticles, medical devices
58
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Ie
BIOCOMPATIBILITY TESTING OF INJECTABLE MEDICAL
DEVICES.
Jeffrey A. Handler, JAH Associates LLC,
Wayne, PA.
Injectable medical devices are used for a wide
variety of indications, including dermal filling in
lipoatrophy patients and for cosmetic reasons, vocal
fold bulking and to control stress urinary incontinence.
Constituents of injectable devices vary, but often
include long-chain polymers such as poly-l-lactic acid
and/or poly-l-glycolic acid as well as excipients such as
carboxymethylcellulose and mannitol. Particle size
varies depending upon the desired effect, and is an
important consideration in the approach to safety
assessment. Resorption time of the injectable device
can vary, but often it can take up to 2 years for full
resorption of all injected materials.
Biocompatibility testing for injectable medical
devices follows standard ISO 10993 and G95-1 memo
approaches, including tests for genotoxicity,
cytotoxicity, irritation and sensitization, and systemic
toxicity. Injection of poly-l-lactic acid and/or poly-lglycolic acid typically results in a localized
inflammatory response and encapsulation of the
device. Accordingly, chronic toxicity tests of 6 months
in rats are typically required to demonstrate safety,
with particular attention to potential migration of
materials to lymph glands and possible granuloma
formation. More recent device approvals have also
included preclinical demonstration of resorption of the
device over time; this can vary significantly depending
upon the size of the particles in the device and location
of implantation.
Many excipients such as mannitol and
carboxymethylcellulose have been used extensively in
many products and a literature search of toxicity, such
as reports of sensitivity to carboxymethylcellulose,
typically suffices to demonstrate safety and what
precautions are necessary based on inclusion of these
excipients in the product.
2011
forward with an unproven experimental agent in
clinical trials. This presentation will focus on the pros
and cons of various non-clinical model systems with
emphasis on how closely these models replicate the
human disease. Detailed discussion will include:
models to choose (xenograft, syngeneic, orthotopic,
GEM); endpoints to measure and importance of
pharmacodynamic evaluations which can be used to
inform one as to which clinical patient populations
could best benefit from a therapy. The importance of
the identification and use of biomarkers of activity
and/or safety early in discovery pharmacology and
toxicology studies will also be reviewed.
IIb
INTRODUCTION TO THE TOXICOLOGY SIDE OF
ONCOLOGY DRUG DEVELOPMENT
Hilary Sheevers
and Vincent Murphy, Aclairo and Array BioPharma.
This presentation is designed to give the toxicologist
new to oncology an overview of what studies are
needed to develop an oncology drug for a serious
indication as noted in the ICH S9 guidance . It will
serve as a refresher or update for those who only
occasionally work in this area. An example will
be presented to demonstrate how nonclinical safety
studies can be modified or excluded per ICH S9
compared to the development of pharmaceuticals
for non-life-threatening chronic indications per ICH
M3. The downsides and upsides to following the
guidance will also be discussed. This section will also
serve as an introduction to the final talk of what to do
when your oncology drug shifts to non-life threatening
chronic indications.
IIa
ONCOLOGY PHARMACOLOGY MODELS: VALUABLE
PREDICTIVE TOOLS?
Patrice Lee, Array BioPharma
Inc, Boulder, CO.
The value of non-clinical cancer pharmacology
models has been a raging debate for decades. Cancers
have been cured in mice and rats many times but
these non-clinical successes have not fully translated
to the heterogeneous clinical oncology disease setting.
The best correlations have been seen with cytotoxic
agents while targeted therapies have seen less
validation in the clinic. Yet, efficacy data in non-clinical
studies can give oncologists the confidence to move
59
SYMPOSIA
ABSTRACTS
IIc
OPTIMIZING LARGE AND SMALL MOLECULE
ONCOLOGY DRUG DEVELOPMENT Ian Pyrah, Amgen
Inc., Thousand Oaks, CA
The presentation will describe the differences and
similarities of small and large molecule drugs in the
context oncology therapeutic development. A detailed
analysis of the differential burden placed on drug
development between the ICHS9 guideline versus
ICHS6/ICHM3 will be presented, and strategies for
switching between the two development paths will be
discussed with examples from both the large and small
molecule classes. Of particular concern for transition
from an oncology indication to a non-oncology
indication is the requirement for carcinogenicity
studies which are costly and time consuming. Potential
strategies for managing carcinogenicity risk will be
discussed.
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
IId
WHEN TO CHOOSE ICH M3(R2) FOR THE
DEVELOPMENT OF ONCOLOGY PRODUCTS
Todd
Palmby, US FDA, CDER, Silver Spring, MD
The recently finalized ICH S9 guidance provides
stakeholders and regulators a recommended pathway
for nonclinical development of drugs and
biopharmaceuticals for use in oncology indications for
advanced cancer. Development programs for
investigational drugs and biologics can impinge on
multiple indications including advanced cancer as well
as less serious conditions for which the life expectancy
is long enough to warrant more substantial nonclinical
testing. In addition, development of new therapies for
certain oncology indications may improve the clinical
outcome in the patient population(s) being studied,
thereby changing the life expectancy for those
indications. The goal of this discussion is to provide a
framework for understanding when ICH M3(R2) may
be more suitable for a given development program
versus the more abbreviated program described in ICH
S9.
2011
seen in human populations, with sensitive as well as
resistant individuals being represented. The NTP has
used the F1 hybrid B6C3F1 mouse for toxicity and
carcinogenicity testing for over 40 years. Much like
inbred mice, the B6C3F1 mouse is isogenic. However,
the B6C3F1 mouse represents only a single genetic set,
and while useful because of its genetic uniformity, it
has proven to be a liability in toxicity testing because
of a genetically related exaggerated liver tumor
background incidence and response to test agents.
Over the last decade, the use of genetically-modified
mice in toxicology studies has dramatically increased.
These mice, which have genetic modifications specific
for cancer, provide another model in which the effect
should be due to the effect of compound on the
genetic modification, rather than the background
strain of mouse. The most commonly used genetically
modified mice (rasH2 transgenic, p53 heterzygous
knockout and Tg.AC mice) will be discussed and their
relative strengths and weaknesses compared.
IIIb
RAT MODELS IN TOXICOLOGY STUDIES
Paul-Georg
1
Germann1 and Dr. Klaus Weber2
Senior Vice
President, Discovery to Preclinical Development,
Nycomed GmbH, Byk-Gulden-Sr. 2, 78467 Konstanz,
Germany; 2Head of Pathology, Harlan Laboratories,
Zelgiweg 1, 4452 Ittingen, Switzerland
Due to many factors the selection of the
appropriate rat model for toxicology studies has
sometimes been a difficult decision. There are
numerous advantages and disadvantages for each of
the available strains and stocks that may be
considered. The most commonly used rat models
include the Fischer 344, Sprague Dawley, Wistar,
Brown Norway, and Long Evans strains. Unlike mouse
models, transgenic rat models have not been
commonly used. This presentation will discuss the
advantages and disadvantages of these various rat
models and the most appropriate rat model for
different types of toxicology as well for pharmacology
studies.
IIIa
MOUSE MODELS IN TOXICOLOGY STUDIES. Peter C.
Mann, Experimental Pathology Laboratories, Inc.,
Seattle, WA.
Many toxicologists use outbred mice in their toxicity
and carcinogenicity studies. The many years of using
outbred mice, such as the CD-1, has permitted
development of large databases of background lesions
that can be useful in interpreting study outcomes.
Because outbred mice are genetically undefined, their
use in toxicology screening studies represents an
uncontrolled variable when the experimental goal is to
test a single variable: the test agent. Consequently, it
can be argued that one cannot tell if an observed
response is due to genetic or non-genetic causes.
Proponents for toxicity testing in an outbred stock
consider that the genetic heterogeneity in their
random-bred mice reflects genetic heterogeneity in
human populations and that at least a few mice will
respond to the test agent with a relevant signal if that
agent has human health consequences. Geneticists
have argued for several years that the genetically
undefined outbred mouse is the wrong animal model
for routine toxicity studies and a better strategy would
be to use a small selection of inbred strains without
having to increase the number of test animals. Since
inbred mice of a given sex are isogenic (i.e., genetically
identical) the toxicologist has control of an important
test variable. It is further argued that the genetic
spectrum provided by multiple inbred strains is a
realistic representation of the type of genetic diversity
IIIc
DOG MODELS IN TOXICOLOGY STUDIES. Dr. Klaus
Weber Harlan Laboratories Ltd., Itingen, Switzerland
Beagle dogs of different breeders were used over 25
years at Harlan Laboratories Ltd. Switzerland. There is
little literature on background data available.
Therefore, in-life data,
hematology, clinical
biochemistry and urinalysis data, gross lesions, organ
weights and histopathology data were collected for the
Hsd: DOBE beagle dog and compared with data from
animals used in toxicology studies from 9 different
60
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
breeders.
The data were analysed according to study lengths
including 2-, 4-, 13-, 26-, 39- and 52-Week studies.
Furthermore, the data were compared for similar ages
in steps of 2 months (e.g. age: 5-7 months, 8-9 months
etc).
Major differences to other strains consisted of a
different onset of maturation in males, i.e. in 4 week
studies there were only 9.56% of the DOBE beagles
immature compared to 19.75% of dogs from other
sources. In 13-Week studies, 1.72% of the DOBE males
were still immature vs. 7.46% from other strains.
Interestingly, tubular hypoplasia in testes is a not often
encountered in some strains whereas in others, this is
the case. For females, the differences were not as
significant.
It is noteworthy, that beagle arteritis is only an
exceptional finding in the DOBE strain. Over the years,
it was recorded in only a few cases.
2011
pharmacology, and integration of all available data,
including historical control data. All information
should be taken into consideration when selecting the
best nonhuman primate model for your studies.
IVa
CDER/CDRH
REGULATORY
PERSPECTIVE
ON
COMBINATION PRODUCT DEVELOPMENT Kathy Lee,
Ph.D., US FDA-CDER, Bethesda, MD
For “traditional” medical products, a single set of
regulations governs the review and regulation of the
product.
In the case of combination products;
however, the regulations associated with each Center
are available for use and are applied as necessary to
insure the most appropriate control of the potential
risk to the treated population and/or user. The
applicable regulations range from those associated
with non-clinical studies (Good Laboratory Practices) to
conduct of clinical trials (informed consent, clinical trial
design and reporting, institutional review boards and
investigator selection) to manufacturing (cGMPs and
QSR), and are dependent on the lead Center.
The work necessary to bring a combination product to
market incorporates a complicated regulatory process
involving interactions with at least two Centers within
FDA.
Because of differences in legal/regulatory
requirements between the various Centers, the nonclinical and clinical evaluation of a combination
product can be a more difficult, but not
insurmountable task. This presentation will attempt to
outline some of the similarities and differences
between traditional and combination products, as well
some of the similarities and differences between the
Centers and how these impact the evaluation and
regulation of combination products.
IIId
NONHUMAN PRIMATE MODELS IN TOXICOLOGY
STUDIES
Kevin S. McDorman, Charles River
Laboratories
Studies using nonhuman primate models of toxicity
are becoming more common. This is partially due to
the types of test articles being examined as well as the
need for comparison to the human which is often the
end-user of the test article being evaluated. More
recent applications of nonhuman primate models in
toxicology include developmental and reproductive
toxicology, imunotoxicology, inhalation/respiratory
toxicology, neurotoxicology and neurobehavioral
toxicology. Although the cynomolgus macaque has
become the most commonly used nonhuman primate
model, several other models are available. These
include the rhesus macaque, squirrel monkey, and
marmosets. Background pathology findings are
commonly observed in nonhuman primate toxicology
models, and are defined as spontaneous lesions,
normal physiologic variations, and concurrent natural
diseases or pathologic changes that may or may not be
influenced by test article administration. In addition,
background findings can be influenced by age, supplier
and/or geographical source, genetics, and husbandry
practices.
Distinguishing normal clinical and
anatomic/morphologic variability from test articleinduced changes is critical, and it is the responsibility
of the pathologist to determine which clinical
pathology, gross and histopathology observations
should be designated as background findings in each
study or series of studies. Balanced and accurate
interpretations require experience with the nonhuman
primate model, knowledge of the test article and its
IVb
PRECLINICAL TESTING REQUIREMENTS FOR STENTS: A
CHANGED REGULATORY LANDSCAPE
John Dooley,
Ph.D., Codman & Shurtleff, Inc. (Division of Johnson &
Johnson), Spring House, PA
The CYPHER® Sirolimus-eluting Stent was the first
drug-eluting stent (DES) to receive regulatory approval
in Europe (CE Mark 2002) and the US (PMA Approval
2003). During development and approval of CYPHER,
no Guidance Documents were in place, and preclinical
testing requirements for IDE and PMA approval were
negotiated with the FDA. The interactions with the FDA
and the preclinical testing conducted on CYPHER Stents
will be presented and compared to the
recommendations in the recent FDA Guidance
Document on DES, as well as our ongoing interactions
with the FDA and preclinical testing being conducted
on our NEVO™ Sirolimus-eluting “Reservoir” Stents.
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IVc
REGULATION AND NONCLINICAL ASSESSMENT
STRATEGIES FOR DRUG-DRUG COMBINATIONS
INTENDED FOR COADMINISTRATION
Timothy
Hummer, PhD, DABT, US FDA, CDER, Silver Spring, MD
This Presentation will focus on the nonclinical
studies recommended to support clinical investigation
and approval of drug-drug and drug-biologic
combinations, including fixed-dose combination
products, copackaged products, as well as some
adjunctive therapies.
The extent of nonclinical
requirements is dependent on the amount of available
nonclinical and clinical information for each individual
drug and the combination. Accordingly, varying
amounts of additional nonclinical information will be
required to support the coadministration of two or
more marketed drugs; a marketed drug with an
unmarketed investigational drug; and two unmarketed
investigational drugs.
Recommendations for the
codevelopment of two or more unmarketed
investigational drugs will also be highlighted.
2011
Vc
A HUMAN IMMUNE SYSTEM IN THE MOUSE:
CURRENT STATE OF THE MODEL AND RESEARCH
POTENTIAL Kristina Howard, D.V.M., Ph.D., US FDA,
Bethesda, MD
This talk will focus on a mouse model with a human
immune system. The background and derivation of
various humanized mouse models will be introduced.
Discussion will focus on potential uses in drug
development including better predicting the biologic
effects of therapeutic proteins, monoclonal antibodies,
and other pharmaceuticals in humans.
Vd
HUMANIZED DRUG METABOLIZING ENZYME MOUSE
MODELS – POTENTIAL APPLICATION IN SAFETY
ASSESSMENT
Alema Galijatovic-Idrizbegovic, Ph.D.,
Merck & Co., Inc., West Point, PA
Nonclinical development of drug candidates may be
confounded by species differences in drug metabolism.
Metabolites formed in humans may be unique as
compared to nonclinical test species. Metabolism in
nonclinical species may also result in unique or
disproportionate metabolites leading to toxicities of
questionable human relevance. Genetically engineered
mouse models that express human P450 enzymes
could provide one potential approach to minimize the
impact of metabolite related challenges in drug
development. These models may have the ability to
generate major human metabolites and eliminate or
reduce the formation of rodent specific metabolites.
Prior to utilization of such models, it is important to
qualify by characterizing protein expression,
establishing whether the model generates an in vivo
metabolite profile more closely related to that of
humans than the wild-type mouse, verifying genetic
stability, and evaluating animal health. Since the
current strategy for handling metabolite challenges
through direct administration of metabolites is
expensive and can significantly extend development of
drug candidates, identifying an appropriate human
P450 expressing model could provide a number of
benefits. An in vitro and in vivo approach has been
utilized for an evaluation of humanized CYP3A4 drug
metabolizing mouse model and its potential utility in
toxicology studies to address exposure issues with a
highly abundant human metabolite for Merck
Compound A for which adequate coverage could not
be obtained in routine toxicology species.
Va
USE OF TRANSGENIC MOUSE MODELS FOR PK AND
SAFETY PROFILING OF COMPOUNDS
Nico Scheer,
Ph.D., Taconic-Artemis GmbH, Cologne, Germany
Transgenic mouse models humanized for key
proteins involved in drug metabolism and disposition
can help to improve the selection of the most
promising drug candidates in preclinical development
by reducing the impact of species differences. Thereby
such models can make a positive contribution to
reducing clinical stage attrition rates by removing
problematic compounds earlier in development. This
presentation will summarize the state-of-the-art in this
field, describe different applications of this approach
and provide some selected examples on the use of
these models.
Vb
MOUSE MODELS WITH HIGHLY HUMANIZED LIVERS:
CURRENT APPLICATIONS AND FUTURE DIRECTIONS
Markus Grompe, M.D., Oregon Health & Science
University, Yecuris Corporation, Portland OR
Chimeric mouse models with highly humanized
livers hold considerable promise for more predictive
preclinical studies in small animals. Several transgenic
mouse strains capable of being repopulated by human
hepatocytes will be presented, in particular albuminuPA transgenics and Fah knockouts. Validated
applications will be described, as well as ongoing
further development in the areas of drug
metabolism/pharmacokinetics,
toxicology,
and
infectious diseases.
Ve
FDA PERSPECTIVE ON HUMANIZED ADME MODELS
Mark W. Powley, Pharmacologist, Division of Anti-Viral
Products, US FDA
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This brief presentation will provide regulatory
perspective on use of humanized ADME models. The
primary focus will be potential regulatory applications
in non-clinical drug development. Key questions for
regulatory decision making will be discussed as will the
need to understand potential liabilities resulting
from genetic modification.
2011
findings should be descriptive to allow for
interpretation. All of these factors should be
considered at the time of protocol review, especially if
the in-life portion of a study and the microscopic
portion of the study are going to be conducted at
different locations.
VIc
FIRST DO NO HARM: NONINVASIVE MEASURES OF
STRUCTURE AND FUNCTION IN OCULAR TOXICOLOGY
AND DRUG DISCOVERY Jeff Jamison, Ophthy-DS, Inc.
and MPI Research, Mattawan, MI
This presentation will review methods of
noninvasive in vivo techniques used to evaluate the
health of the retina and extra-ocular tissues relevant to
models of ocular disease and toxicology. Methods and
examples of imaging of ocular tissues using slit lamp,
fundus photography, retinal angiography and OCT
(optical coherence tomography) will be presented.
Techniques for assessing retinal function such as
electrophysiology of the retina (ERG), the Optokenetic
response and operant conditioning using visual
discrimination tasks will be reviewed. This talk will
concentrate on the usefulness of various techniques to
capture specific endpoints with various instruments.
Where possible, case examples of induced ocular
pathology or pathology due to drug toxicity will be
reviewed or relevant examples from the literature will
be cited. In addition, species differences will be
highlighted as well, with most examples coming from
rodents, rabbits, canine and non-human primates.
VIa
OCULAR TOXICITY IN AN ONCOLOGY THERAPEUTIC:
OBSTACLES AND IMPACT TO DEVELOPMENT
Vince
Torti, Pfizer, Inc., LaJolla, CA
Covered in this talk will be a case which significant
ocular toxicity was found associated with an oncology
therapeutic. Ocular toxicity was first observed in a 1month IND-enabling study and occurred in the dog
retina only despite both dog and rat studies being
performed. First indications of adverse effects were
observed clinically after 10-20 days of daily (QD)
exposure and were validated via microscopic
pathology and electroretinogram (ERG) assessment.
Topics covered for this case will be: a complete review
of the preclinical toxicology data and various
considerations from the preclinical, clinical, and
regulatory perspectives impacting development.
Specifically, considerations of target pharmacologybased effects, non-clinical assays useful for earlier
detection of ocular toxicology, potential clinical
monitoring assays, and an overall assessment of risk
for pursuing oncology clinical studies will be discussed.
VIb
DETECTION OF MICROSCOPIC FINDINGS OF OCULAR
TOXICITY James A. Render, NAMSA, Northwood, OH
This presentation will review factors that are
involved in detecting microscopic ocular findings
caused by toxicity. An accurate interpretation of
microscopic ocular findings requires an understanding
of comparative ocular anatomy, spontaneous ocular
findings, iatrogenic ocular findings, microscopic ocular
artifacts and possible toxicological changes for a given
compound, chemical or medical device. Unlike other
organs, except for the skin, findings involving the eye
are often identified clinically and it is up to the
pathologist and the histotechnologist to capture the
clinical finding in a histologic section. Therefore, in
order to have a microscopic correlation, it is important
for the study pathologist to be aware of clinical ocular
findings at the time of necropsy, tissue trimming and
microscopic examination. Detection of microscopic
changes is not possible without the preparation of
good quality histologic sections. These sections require
proper ocular orientation and minimal tissue artifacts.
Terms used to denote clinical and microscopic ocular
VId
CLINICAL AND NONCLINICAL CORRELATES OF OCULAR
TOXICITY:
EVALUATION
AND
REGULATORY
CONSIDERATIONS
Maria I. Rivera, UD FDA CDER,
Silver Spring, MD
This talk will explore the relationship between
ocular findings from nonclinical studies and the
occurrence or lack of occurrence of such findings in the
clinical setting. In addition, the presentation will
describe the evaluation of both nonclinical and clinical
findings from a regulatory perspective and how these
findings could potentially impede further clinical
development. The talk will present some examples of
findings observed in the nonclinical setting, the factors
taken into consideration to decide if development
should or should not continue, and the required
clinical monitoring program when the trials were
allowed to proceed.
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VIIa
AN INDUSTRIAL PERSPECTIVE ON MUTAGENICITY
MODELING
Catrin Hasselgren, Principal Scientist,
AstraZeneca R&D, MoIndal, Sweden
The application of computational methods for risk
assessment of compounds is common practice for
Pharmaceutical companies today and ranges from
early discovery (library design) to post marketing (e.g.,
qualification of degradants). Different phases in the
drug development require different levels of
information and an extensive toolbox of methods,
each suitable for the stage at which it is used, is
desirable. This talk will briefly cover the commercial
tools available for genotoxicity prediction. It will also in
more detail describe how these and internally
developed tools are used within AstraZeneca
throughout the Drug development process.
2011
examples from our own studies of teratogens and
mutagens that illustrate the two main issues that most
influence the ability of computational algorithms to
determine risk: the biological data used to develop the
QSAR relationships, and the generality of the questions
being asked of these algorithms.
Topics covered
1. Prediction of mutagenicity - issues with the standard
structure-based approaches
2. Prediction of arylamine mutagenicity using a novel
reaction-based approach
3. Prediction of teratogenicity - issues with standard
structure-based approaches
4. Prediction of triazole antifungal mutagenicity using a
novel approach based on a comprehensive analysis
of molecular descriptors and recursive partitioning.
5. A summary of what these studies tell us about the
capabilities and limitations of computational
methods for predicting toxicity.
VIIb
APPLICATION OF COMPUTATIONAL MODELS FOR
TOXICOLOGY IN PHARMACEUTICAL DEVELOPMENT
Nigel Greene Ph.D., Pfizer, Inc., Groton, CT
For many years the pharmaceutical industry has
been developing and using computational models for
genotoxicity and these are now routinely used in the
identification and control of genotoxic impurities.
More recently the application of these models has
been gaining increasing regulatory interest and
acceptance. However, there is also a desire to expand
computational models to other areas of toxicology
such as hepatotoxicity. This presentation will touch on
some of the recent advances in in silico models for
toxicity and highlight some industry perspectives on
their successful application in drug discovery and
development.
VIId
REGULATORY UTILITY OF IN SILICO PREDICTIONS:
PERSPECTIVES FROM AN FDA REVIEWER
Mark W.
Powley, Ph.D., US FDA, Silver Spring, MD
The presentation will focus on the regulatory utility
of in silico predictions for evaluating potentially
genotoxic impurities. Primary areas of discussion will
be current (Q)SAR approaches, the FDA internal
process for evaluating impurities, and the role of in
silico predictions in regulatory decision making.
Limitations of the various approaches, areas of
regulatory concern, opportunities for improvement,
and suggestions for regulatory submissions will also be
covered.
VIIe
THE EXPERIENCE OF THE US FDA/CDER (Q)SAR
GROUP: CRITERIA FOR USING COMPUTATIONAL
TOXICOLOGY FOR CDER REGULATORY DECISIONS R.
Daniel Benz, Ph.D., US FDA, CDER, Silver Spring, MD
This presentation will recommend minimum
requirements
for
predictions
from
(Q)SAR
computational toxicology software models to provide
results acceptable for regulatory consideration, e.g.,
how diverse training sets should be, how good
coverage is necessary, and what level of sensitivity
(confidence for negative predictions) is acceptable.
Also to be presented is why it is useful to use multiple
computational platforms to reach an overall
conclusion, how many software programs are enough,
and how conflicting predictions can be interpreted.
Other information that needs to be considered when
evaluating the validity of computational results are
how similar the training chemicals that are the basis of
VIIc
COMPUTATIONAL METHODS BASED ON CHEMICAL
STRUCTURE– HOW USEFUL ARE THEY?
Oliver Flint,
Ph.D., Bristol-Myers Squibb, Princeton, NJ
Since Hansch’s first studies in the mid 60’s showing
a relationship between the lipophilicity (LogP) and
biological effect of toxic agents, it has been the goal of
computational chemistry (chemometrics) to predict
the safety of chemicals using molecular descriptors. In
the past 50 years software programs for determining
toxic risk have evolved to the point that several
important products are currently being used by
Pharma and by the regulators who review our drug
submissions. We have learned that there appears to be
a practical limit on our capacity to predict toxicity, and
this limit is not determined by the capacity of our CPUs
to process data or by our ability to describe molecular
properties. In this presentation we will provide
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
the prediction need to be to the chemical of interest
and the benefit of comparing the results of related
(Q)SAR models. Finally, the need for industry
submitters and government reviewers to use the same
software versions, models and interpretation will be
emphasized.
2011
indications, validating targets, and use in small
compound drug discovery, toxicity assessment,
biomarker identification, and pre-clinical studies. The
technology is used in basic science programs to extract
large amounts of cellular data information to better
understand cell functions and mechanisms of actions
in developmental biology and target-based
identification in diseased tissue. This presentation will
discuss the use of image analysis techniques and the
application of the data in predictive toxicology models.
VIIIa
USE OF IMAGING BIOMARKERS IN DRUG DISCOVERY
AND IN RESEARCH AND DEVELOPMENT PROGRAMS
Dr. Norman Barlow and Dr. Xiaoyou Ying, Sanofi,
Bridgewater, NJ
VIIIc
USE OF DIGITAL PATHOLOGY TO PROVIDE
AGGREGATE MEASUREMENTS OF EFFICACY AND
TOXICITY IN NONCLINICAL AND CLINICAL STUDIES
Dr. David Young, Flagship Biosciences, LLC, Boulder, CO
The decision to advance an early-stage compound
into formal preclinical testing depends on confidence
in mechanism, efficacy and toxicity profiles. A
substantial percentage of this confidence comes from
histopathology interpretation, as the local tissue
environment contains strong signals of both efficacy
and toxicity. Accessing this tissue information is made
difficult by biological variability across organs and
tissues, an insufficient pool of pathology experts
working in discovery, and the high subjectivity and
individual isolation of microscope-based observations.
This presentation will discuss how whole-slide imaging
and quantitative analysis by trained pathologists are
improving early-stage decision-making and its
application to resulting clinical studies.
Imaging biomarkers have become valuable tools in
drug discovery and research and development
programs within pharmaceutical companies. They are
useful to help monitor the efficacy and the toxicity of
test substances in nonclinical studies. These types of
biomarkers are being requested more and more by
regulatory agencies.
However, before imaging
biomarkers can be used as surrogate endpoints in
clinical trials, they must be confirmed in nonclinical
animal models. Types of imaging biomarkers that are
currently available and are in use in research programs
today will be reviewed in this presentation.
Developments that may be promising to help monitor
the effects of test substances in nonclinical models and
patients will also be discussed.
VIIIb
USE OF IMAGING BIOMARKERS IN BASIC RESEARCH
AND APPLICATION TO THE DEVELOPMENT OF
PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK)
MODELING FOR RISK ASSESSMENT
Dr. O. Joseph
Trask, Jr., The Hamner Institutes for Health Sciences,
Research Triangle Park, NC
The advancements in modern-day cellular imaging,
along with genomic information, has allowed scientists
to probe deeper into the underlying mechanisms of
cellular functions, effects of protein transcription, cell
pathway signaling, and ultimate fate of the cell's life
cycle all in an effort to better understand the
developmental processes and finding treatment or
even cure of human diseases. It has been a little more
than a decade since automated fluorescent microscopy
image analysis or better known as High Content
Screening (HCS) was introduced to the scientific
community, but the approach has been occurring for
almost 20 years, the knowledge and lessons learned
over this time has provided an insight of where the
technology is today and what to expect in the coming
years. Today, almost every pharmaceutical company
has implemented some version of HCS into the drug
discovery process, as well as many biotechnical firms
with the promise of identifying new drug target
VIIId
ANALYZING DISCRETE BIOLOGICAL ENDPOINTS IN
SOLID
TUMORS
UTILIZING
NOVEL
DIGITAL
PATHOLOGY APPROACHES
Joseph Krueger, Ph.D.,
Director of Biology, Flagship Biosciences
Although
experimental
molecular
targeted
therapies (MTTs) for oncology are based on a strong
biological rationale for the target, they often fail in
clinical trials due to lack of efficacy. A significant
cause for a disconnect between biological rationale
and clinical efficacy is the inability to use preclinical
drug discovery models in a manner which represents
the true nature of clinical disease. To translate the
appropriate disease hypothesis from early discovery
into clinical trials, preclinical models must emphasize a
systems biology approach, which anticipates biological
processes which can lead to adaptation and resistance
to a therapy. Many drug resistance mechanisms are
dependent on tumor microenvironment directed
processes, and thus are discrete, context dependent
events. These biological processes are often focused
on a particular tumor compartment, such as tumor-
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
associated stroma, blood vessels, areas on
inflammation, necrotic regions, and groups of tumor
cells with regional phenotypic behavior which can best
be observed using pathology based approaches.
Classical IHC quantification approaches, which take an
average expression across a slide, do not convey
sufficient information about these discrete events and
do not account for the inherent variability in the
tumor. Digital pathology approaches can be used to
efficiently detect these discrete biological endpoints,
identify biomarkers which represent these processes,
and quantify these biomarkers. These approaches can
be directly translated into a clinical companion
diagnostic, which can facilitate better prediction of a
patient’s potential for response to a therapy, and
provide rationale for patient selection that will enable
clinical success.
2011
the current realities and challenges in the risk
assessment process and highlight the pragmatic ways
in which the ELSIE database could improve the process.
IXc
THE MATERIAL SELECTION PROCESS FOR DRUG
PRODUCT PACKAGING/DEVICES AND THE ELSIE
MATERIALS INITIATIVE
Andrew Feilden,
AstraZeneca, Loughborough, Leicester, UK
Leachables, chemicals that migrate from the
materials into the drug product, can cause safety
toxicity concerns and/or stability issues from
unwanted reactions with the drug product. Testing is
required to demonstrate the quality and safety of the
drug product at end-of-shelf-life. To meet global
supply requirements, a shelf-life period of 2 or more
years is normally desired. A mis-step in the selection
of packaging or device materials can lead to costly
material change issues and delayed launch schedules if
detection of unwanted leachables occur during late
stage testing. A QbD approach to the selection of
materials used to package drug products or to
construct medical devices that deliver drug products is
proposed to de-risk the material selection process.
The presentation will provide concrete examples and
will discuss industry initiatives currently under
development (ELSIE materials database) to help in the
material selection, testing, and evaluation of
extractables and leachables.
IXa
INTRODUCTION AND BACKGROUND TO ELSIE AND
THE ELSIE DATABASE
Laurie Iciek, Ph.D., Principal
Toxicologist, MedImmune, Gaithersburg, MD.
Introduction and background to the ELSIE
consortium, impetus and development of the database
concept, objectives of the database effort, on-going
work and future plans.
IXb
SAFETY ASSESSMENT OF EXTRACTABLES AND
LEACHABLES:
CHALLENGES AND APPROACHES
William P. Beierschmitt, Pfizer Worldwide Research &
Development, Groton, CT
An essential, critical component of the registration
package for a parenteral product that is addressed by
the toxicologist is the risk assessment of leachables
and extractables. From a toxicology perspective, while
extractable data can provide valuable information (i.e.,
what chemicals might migrate into the drug during
storage), formal risk assessments are typically only
performed on leachables (i.e. what chemicals did
migrate into the drug during storage). The basic
premise of this procedure is to assess the potential risk
to humans resulting from unintentional exposure to
the chemicals that migrate into drug product from
packaging. Early involvement of the toxicologist in
leachable and extractable studies from the earliest
experimental planning stage through the data
collection greatly facilitates arriving at a timely and
successful assessment of these chemical impurities.
Continued improvement in communication and
information exchange with manufacturers regarding
constituents/chemical make up of packaging
components would also facilitate the risk assessment
process. This presentation will provide an overview of
IXd
DEMONSTRATION OF THE ELSIE DATABASE
Steve
Beck, GlaxoSmithKline Research & Development,
Ware, Hertfordshire, UK
Real time demonstration of ELSIE database.
ELSIE has designed a database which contains current,
searchable, safety information for a wide range of
extractables and leachables. It is ELSIE's intention to
create a database that will support companies’ safety
assessments produced as part of regulatory
submissions and be viewed as a credible and valuable
resource by industry (and regulators) worldwide. This
presentation will include a practical demonstration of
the prototype database, illustrating its function with
the use of specific examples.
Xa
INTRODUCTION TO OLIGONUCLEOTIDE THERAPEUTICS:
STRUCTURE, FUNCTION, AND APPLICATIONS
Scott
Henry, Ph.D., DABT, Isis Pharmaceuticals
Oligonucleotide therapeutics endeavor to become a
broadly applicable platform for novel drug discovery.
The opportunity is that this technology can potentially
take advantage of the known human gene sequence
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
and the ever-increasing knowledge of the genetic basis
of disease to help patients in ever more selective ways.
Many diseases that are difficult to target with standard
small molecule- or protein/antibody-based therapies
lend
themselves
to
oligonucleotide-based
therapeutics.
In the past 5 to 10 years, there has been
tremendous advancement in understanding the
complex function that RNA plays in the cell. This has
led to structural modifications that optimize potency,
tolerability, and PK properties of antisense inhibitors
and to the understanding of how to exploit multiple
cellular mechanisms to affect RNA biology. Cellular
mechanisms that lead to reduction in targeted RNA
can be achieved through either DNA:RNA (RNase H) or
RNA:RNA (RISC complex) interactions. Oligonucleotide
therapeutic can be used to alter splicing of RNA, either
skipping exons or including exons. The more recent
discovery of non-coding RNA in cells, such as
microRNAs, and the role they play in regulating the
transcription of larger families of RNA have further
expanded the opportunity. These microRNAs can be
used to supplement or compete for endogenous
microRNAs to either increase or decrease expression.
The potential therapeutic applications of
oligonucleotides are very broad, and limited primarily
by oligonucleotide uptake by target cell types. Still,
pharmacology has been demonstrated in liver, fat,
tumors, kidney, and muscle following systemic
administration. Indications range from cancer to
metabolic disease, cardiovascular disease and other
rare genetic diseases. There is also the potential for
local application for CNS, ocular, and pulmonary
diseases.
2011
Xb
OLIGOS: AKIN TO SMALL MOLECULES OR BIOLOGICS?
Cindy L. Berman, Ph.D., Independent Consultant
At the FDA, oligonucleotide therapeutics are
currently regulated under CDER-like guidelines based
on the fact that the molecules are chemically
synthesized. On the other hand, ICH S6 indicates that
the
guidance
for
biotechnology-derived
pharmaceuticals may be applicable to oligos. In reality,
oligonucleotides have many properties that are distinct
from either small molecules or biotechnology-derived
products. A ‘polymeric’ structure that utilizes basic
endogenous building blocks distinguishes oligos and
biologics from small molecule drugs. This structure
and the inherent size of the molecules impact chemical
purity, distribution, metabolism, and the toxicity of the
metabolites. Pharmacodynamic properties on most
oligos are dependent on the tissues concentrations
and pharmacokinetic tissue half-lives are often long,
thus activity may not correlate directly with plasma
concentration. In addition, like biologics, many oligos
are rationally designed to modulate specific human
targets. This can confer not only specificity to the
target, which decreases off-target toxicity, but also
specificity to primates, which impacts the nonclinical
development program.
This presentation will explore these and other
similarities and differences between oligonucleotides,
small-molecule drugs, and biologics and will examine
the applicability of regulatory guidances to the
nonclinical development of ON therapeutics.
Xc
CLASS
EFFECTS
AND
OTHER
SPECIAL
CONSIDERATIONS IN THE SAFETY TESTING OF
OLIGONUCLEOTIDE THERAPEUTICS Doug Kornbrust,
Ph.D., Preclinsight
The first generation of oligonucleotide (ON)
therapeutics was largely based on structures
containing a phosphorothioate (PS) backbone, which
conferred a spectrum of toxicities that were generally
independent of the nucleotide sequence and, hence,
are referred to as “class effects”. These toxicities and
the current understanding of their mechanisms will be
profiled. In more recent times, the ON therapeutic
world has expanded substantially through optimization
of medicinal chemistry and with the emergence of
various other subclasses and mechanisms of action,
including
aptamers,
Toll-like
receptor
agonists/antagonists, and siRNAs, with even more
applications on the horizon. These newer types of ONs
may share some of the PS class effects, depending on
the chemistry employed, but also exhibit unique
toxicologic properties. As the potency of ONs is
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
increasingly improved, the need to characterize
adverse effects stemming from exaggerated
pharmacology has expanded and evolved. In addition,
for an increasing percentage of ON programs,
specialized delivery formulations have been employed.
This growing diversity has created new challenges for
addressing the safety of these products.
This
presentation will summarize the evolution of
oligonucleotide safety evaluation from a historical
perspective and provide general insights into
appropriate strategies for various subclasses.
2011
Xe
OLIGONUCLEOTIDE THERAPEUTICS: A PHARM/TOX
REVIEWER’S PERSPECTIVE
Robert T. Dorsam, Food
and Drug Administration, CDER
Oligonucleotide therapeutics are currently being
developed for a wide variety of disease states. This
class acts by various mechanisms of action and
comprises different backbone chemistries that
contribute to their diverse pharmacologic and
toxicologic activities. In addition, they may be
delivered by many routes of administration and in
complex formulations. All of these factors may confer
pharmacokinetic or pharmacodynamic advantages but
may also present specific toxicity profiles or safety
considerations, which can be addressed by careful
design of the non-clinical studies.
Like most therapeutic classes, a case-by-case
approach to the non-clinical development plan is
warranted for oligonucleotide therapeutics. With a
primary goal of patient safety, pharm/tox reviewers
must consider several elements in their safety
assessment. This presentation will include a reviewer’s
perspective on how a safety assessment is made, along
with how elements of non-clinical studies may be
tailored to address safety considerations with
oligonucleotides. In addition, an overview will be given
of internal and external initiatives in which pharm/tox
reviewers participate in order to maintain an informed
and consistant approach to the review of an evolving
class of drugs with the goal of assisting their safe entry
into clinical trials.
Xd
PRECLINICAL SAFETY ASSESSMENT OF INHALED
OLIGONUCLEOTIDES
Nicolay Ferrari, Ph.D.,
Pharmaxis Ltd
Oligonucleotide (ON) drug candidates are currently
being assessed in clinical trials as new therapeutic
agents for many indications. Currently, the vast
majority of strategies for the development of ON have
focused on systemic administration, in particular in the
field of oncology or metabolic and cardiovascular
diseases. The toxicology and pharmacokinetics of ON
following systemic administration (e.g., intravenous
and subcutaneous routes of administration) has been
well described. Some pharmaceutical companies and
investigators have explored alternative dosing routes
such as the pulmonary route of administration.
However, there is a relatively little information on the
efficacy, deposition, and tolerability following local
delivery to the lungs via inhalation. Furthermore, the
Pulmonary Division of the FDA indicated having
reviewed only six ON through Investigational New Drug
(IND) or pre-IND application meetings (ref. DIA 2010).
The direct consequence of such limited experience in
the development of inhalation ON is therefore a poor
understanding of 1) the lung response to inhalation of
ON in different species from pre-clinical animal models
to human; 2) the response induced by different ON
types and chemistries/formulations; and 3) the
appropriate methods and readouts needed to
adequately assess and monitor potential toxicity in
human. This has rendered the interpretation of
potential adverse effects caused by inhalation of ON
and their relevance for human safety challenging both
for the industry and the regulatory agencies.
This presentation will summarize the preclinical
safety of inhaled ON and will discuss the challenges
and issues of the development of such drug
candidates.
XIa
THE CHALLENGES AND CONSIDERATIONS OF
HOMOLOGOUS
MOLECULES
USED
IN
BIOPHARMACEUTICAL DEVELOPMENT
Donna Lee,
Ph.D., DABT, Genentech, South San Francisco, CA
Alternative approaches for evaluating the safety of a
biotherapeutic with limited species specificity include
the use of transgenic animals, animal models of
disease, and homologous molecules. A homologous
antibody can be a useful tool for characterizing
preclinical safety if the clinical candidate is active only
in humans or chimpanzees.
However careful
consideration should be given to rigorous and
appropriate characterization of homologs. Both in
vitro and in vivo assessments should demonstrate
similarities between the clinical candidate and
homolog. These may include structural and sequence
properties of the antigen, antibody affinity, and
biologic activities (e.g. signaling comparability, in vivo
PK/PD parameters).
Standard and alternative approaches in the utility of
homologous molecules in various development
68
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
programs will be presented; with focus on a case study
of an anti-B-cell antigen antibody drug conjugate (ADC)
being developed for B-cell malignancies.
A
homologous ADC was generated due to the limited/no
cross-reactivity of the clinical candidate to the human
receptor.
This enabled the use of cynomolgus
monkeys in determining antigen-specific toxicity and
PK/PD in an IND-enabling repeat-dose toxicity study.
Results
from
this
study
confirmed
the
pharmacodynamic effect of the homologous ADC and
established the relevance of using a homologous
molecule for safety assessment of the clinical
candidate.
2011
needs to be given to the most appropriate animal
model for toxicological investigations. A brief review
of the alternatives to traditional toxicology studies will
be discussed. In addition a case study of the utility and
data generated using a transgenic animal for the
toxicological assessment of a biotherapeutic will be
described.
XId
A REGULATORY PERSPECTIVE M. Stacey Ricci, Sc.D.,
US FDA, Silver Spring, MD
The FDA will provide a regulatory perspective on the
challenges and considerations associated with
transgenics, animal models and surrogate molecules
for the development of biological candidates for
therapy.
XIb
ANIMAL
MODELS
OF
DISEASE:
UNIQUE
OPPORTUNITIES AND CHALLENGES
Marque Todd,
DVM MS DABT, Pfizer, Inc., San Diego, CA
Animal models of disease have traditionally been
used in discovery to assess the efficacy of new
potential drug candidates. Drug candidates today are
more complex both in modality (Fc enhanced,
antibody-drug conjugates, fusion proteins, bi-modal
molecules) and in their targets and associated biology
(pathogens, genetic diseases, targets only up-regulated
in the disease state). It becomes difficult in some cases
to justify the use of traditional toxicology studies to
assess these complex drug/target combinations and
this has led to an increased interest in animal models
of disease. The generation of disease models has also
advanced with the ability to genetically engineer
animals to manifest a variety of disease states. Thus,
new questions are being raised: how well do these
models mimic human disease; how can they best be
validated and utilized to assess human safety; and
what are the primary issues and challenges if this
approach is undertaken over the use of more
traditional approaches. A general overview of various
animal models of disease and associated case studies
highlighting the advantages and potential issues will be
given.
XIIa
BIOMARKERS AND TRANSLATION: WHERE ARE
PHYSIOLOGICAL
BIOMARKERS
EFFECTIVE
IN
TOXICOLOGY AND SAFETY ASSESSMENT?
Rob
Wallis, Pfizer, Inc., Groton, CT
This discussion addresses the science around
biomarkers as a translational tool. How well does our
current science support the use of biomarkers as
outcome predictors in clinical trials? Present scientific
methods will be related to animal model selection and
where our science is limited.
XIIb
CARDIAC PHYSIOLOGY AND CARDIOVASCULAR
TOXICITY… DO WE HAVE MODELS AND MARKERS
THAT MAKE SENSE AND WORK
Robert Hamlin,
DVM, Ph.D., Ohio State University, Columbus, OH
What can we say about what we are doing that
grounds us in good conclusions for predicting human
trial results?
What does toxicity look like in our
current cardiovascular data? Our science and our
models will be discussed as a factor determining how
well we can translate toxicology and safety data to
clinical outcome expectations.
XIc
A TRANSGENIC ANIMAL MODEL AS A USEFUL AND
RELEVANT TOOL FOR SAFETY STUDIES: A CASE
PRESENTATION
James Murray, Genzyme,
Framingham, MA
Traditional animal models are the most often used
species for the toxicological evaluation of
biotherapeutics. Investigation into the utility of
alternative animal models has only recently become an
experimental option. With species specificity of
monoclonal antibodies or disease models showing
enhanced and relevant pharmacology, consideration
XIIc
IMPROVING CARDIOVASCULAR ASSESSMENT IN
CANINE TOXICOLOGY STUDIES
Pierre Lainee, Astra
Zeneca, UK, Macclesfield, UK
A review of 100 preclinical studies resulted in
refinement of methodology for canine ECG recording.
Sensitivity comparisons of several methods resulted in
conclusions for including ECG in toxicology safety
studies. The value and benefit of external telemetry
for ECG recordings in toxicology studies will be
discussed in detail and related to recent case examples
in dogs and primates.
69
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
XIId
BLOOD PRESSURE ASSESSMENT AS A MARKER IN
REGULAR TOXICOLOGY STUDIES
Marc Niehoff,
Covance Laboratories, Munste,r Germany
Regular toxicology studies are a challenge when
hyper and hypo tensive compound effects need
sensitive assessment. Current blood pressure
measurement techniques like HDO still require animal
restraint causing stress related increases in
cardiovascular endpoints. This validation study
explores the feasibility of a minimally invasive
approach to continuously measure blood pressure in
conscious, freely moving animals. Furthermore, it
indicates that no adverse histopathological side effects
or changes in clinical pathology are accompanied by
the surgical implantation of the miniature blood
pressure implant.
2011
petroleum substance may not in itself be hazardous.
This is usually because the hazardous constituents are
often reduced to low levels during refining. For
purposes of toxicological evaluation, petroleum
substances can be arranged into groups or categories
of “similar” substances. The rationale for such
groupings is that the petroleum substances within a
group are derived from similar starting materials, have
similar physico-chemical properties and have generally
similar compositions and hazard profiles. Grouping was
used to meet REACH registration and HPV (High
Production Volume) program objectives. The
remaining talks in this symposium will focus on specific
substances / substance groups (categories) and discuss
the approach and interpretation for safety evaluations.
XIIIb
ASSIGNING AN ADI TO WHITE MINERAL OIL: USE OF
PHARMACOKINETIC DATA
Peter J. Boogaard, Shell
International bv, The Hague, The Netherlands
Mineral hydrocarbons (MHC) have important uses in
various food applications, as outlined by United States
Pharmacopoeia (USP) and Code of Federal Regulations
(CFR). MHC residue can be identified in human
autopsy samples, and inflammatory responses in
mesenteric lymph nodes and liver have been identified
in F-344 rats but not in other rat strains or species.
Long-term animal studies have established a SAR and
low hazard potential for MHC.
Comparative
pharmacokinetic studies in F-344 and SD rats and in
human volunteers were used to establish an
appropriate Acceptable Daily Limit (ADI) which has
been provided to the World Health Organization
(WHO) Joint Expert Committee on Food Additives
(JECFA).
XIIe
FUNCTIONAL BIOMARKERS IN THE INTEGRATED
STUDY DESIGN: WHAT MAKES SENSE AND WHEN
Ted Baird, Ph.D., MPI Research, Mattawan, MI
The recent use of integrated study designs has
provided the ability to include functional biomarkers
for safety assessment in early toxicology studies. This
new design approach offers the ability to advance
programs more rapidly. The issues around using this
approach will be addressed using data from recent
validation studies with discussion of how and where
this added effort has value.
XIIIa
OVERVIEW OF PETROLEUM SUBSTANCES
James J.
Freeman, ExxonMobil Biomedical Sciences, Inc.,
Annandale, NJ
Petroleum substances are derived from crude oil by
physical separation (i.e., distillation), which may be
followed
by
chemical
modification
(e.g.,
hydrogenation, cracking, etc.) to achieve desired
performance characteristics and/or emission reduction
goals. There are many different types of crude oil and
each consists of many thousands of constituents,
predominantly hydrocarbons. The composition of the
petroleum substances will be dependent on the source
crude oil itself, hydrocarbon partitioning into distillate
fractions and the subsequent refining steps. It follows
that petroleum substances are of variable chemical
composition (UVCBs). Crude oil contains certain
hazardous constituents (e.g., benzene, polycyclic
aromatic hydrocarbons) which may partition into
different product groups (e.g., fuels, lubricants,
asphalt, etc) due to distillation/refining considerations.
However, despite possible occurrence of such
hazardous constituents, tests may show that the full
XIIIc
RECENT
STUDIES
ON
THE
POTENTIAL
CARCINOGENICITY OF ASPHALT FUMES
Charles R.
Clark, ConocoPhillips Company, Bartlesville, OK
NIOSH-sponsored studies in the 1980s identified
fume condensate from a built-up roofing asphalt as
carcinogenic to mouse skin. However those fumes,
which were generated under laboratory conditions,
were found to be compositionally different from fumes
to which workers are exposed. Advances in fume
generation and collection technology now allow for
collection of sufficient quantities of “field-matched”
fume condensate to conduct lifetime animal bioassays.
The results of bioassays of field-matched fume from
both roofing and paving asphalts will be discussed as
well as studies investigating the role of temperature on
the composition and biological activity of fumes. The
outcome of the International Agency for Research on
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Cancer (IARC) reevaluation of bitumen (asphalt)
carcinogenicity, scheduled for October 2011, will also
be summarized and discussed.
2011
XIIIe
PREDICTION OF TOXICITY BASED ON A STATISTICAL
ANALYSIS OF AROMATIC COMPOUNDS PRESENT IN A
PETROLEUM STREAM Mark Nicolich, Ph.D., Cogimet,
Lambertville, NJ
As part of the US HPV (high production volume)
challenge program, the American Petroleum Institute
summarized data for a variety of toxicity endpoints on
complex petroleum substances and the weight percent
of their aromatic ring class (ARC) using a
chromatographic test referred to as PAC2. We have
developed a series of predictive models based on the
ARC ring profile and basic biological measures such as
body weight to describe and predict repeat-dose and
developmental toxicity endpoints for a number of
petroleum substances. There are 7 models that
predict selected Screening Information Data Set (SIDS)
subchronic and reproductive endpoints and are based
on 39 unique petroleum substances; the correlation
between observed and predicted values are greater
than 0.89 for these models.
There is also a
mutagenicity model that predicts the modified Ames
score as less than 1 or not, this model is based on 242
unique substances and correctly scored over 94% of
the substances tested. The presentation will describe
the development and form of the models, model
efficacy, demonstrate their predictive ability, and
discuss the sensitivity analyses and validation of the
models. We also discuss the domain of applicability of
these models, which is important because of the
relative complexity of the models.
XIIId
HAZARD
CHARACTERIZATION
OF
COMPLEX
PETROLEUM SUBSTANCES
Richard H. McKee,
ExxonMobil Biomedical Sciences, Inc., Annandale, NJ
Most petroleum substances have complex and
variable compositions. As it is not practical to
separately characterize the hazard properties of each
of the constituents, the approach taken by the industry
is to test “representative” substances and use these
data for other “similar” substances. Within the High
Production Volume (HPV) challenge program, it was
necessary to provide information to characterize the
human health hazards of approximately 400 petroleum
substances identified by CAS number. A review of the
existing information, and new analytical and
toxicological data generated as part of the HPV process
afforded the opportunity to consider the extent to
which substances were representative, how these
relate to other substances, and to determine whether
new hazards could be identified. It was known that
certain high boiling substances contained polycyclic
aromatic constituents (PACs), and that petroleum
substances containing these constituents at sufficiently
high levels were dermal carcinogens. A predictive
model was developed which permitted hazard
predictions for PAC-containing substances to be
extended to include repeat-dose toxicity and
developmental toxicity. Because reproductive hazards
could not be predicted from the compositional data, a
number of subchronic toxicity/reproductive toxicity
screening tests were conducted. The presentation will
summarize the previously available data and new
information. A toxicological evaluation of raw and
refined lubricant base oils will be presented as an
example of the use of both predictive modeling and
read-across as a means of characterizing the hazard
properties of petroleum-derived substances.
XIVa
INDUSTRY VIEW POINT OF NONCLINICAL ISSUES IN
DRUG DEVELOPMENT AND NDA Clynn Wilker, Ph.D.,
DABT, Ardea Biosciences, San Diego, CA
An overview of industry’s perspective of nonclinical
aspects of drug development and NDA will be
presented. Challenges of drug development under the
current corporate and regulatory environment will be
provided. The presentation will include duration and
cost of drug development, challenges of working with
CROs, and differences in small vs large pharmaceutical
companies on how drug discovery and development is
handled. Examples will be given.
71
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
XIVb
IND AND NDA REVIEW PROCESS – PERSPECTIVES
FROM A PRIMARY REVIEWER
Amy Ellis, Ph.D., US
FDA, CDER, OND, Silver Spring, MD
The presentation will focus on IND packages, format
and content of NDA per electronic Common Technical
Document (eCTD), NDA review process, and
accelerated review process. The speaker will discuss
key aspects of the primary review process and
highlight challenges encountered in developing a
safety recommendation from scientific and
adminsitrative perspectives.
2011
how relative bioavailability can be addressed for
dermal exposures, and how less-than-lifetime
exposures might be considered. In addition, recent
work has focused on how TTC might be used to
support complex mixtures such as botanical extracts,
and how the principles of TTC might be extended to
address local effects such as allergic contact dermatitis
and effects in the respiratory tract following inhalation.
This talk will provide an overview of how these issues
have been addressed and what opportunities remain
for further expansion of TTC as a first-tier risk
assessment tool to evaluate and substantiate human
safety of low-level exposures and appropriately focus
societal resources to avoid unnecessary animal testing.
XIVc
NDA
PROCEDURES
–
SECONDARY
REVIEW
PERSPECTIVES
Lynnda Reid, Ph.D., US FDA, CDER,
OND, Silver Spring, MD
The presentation will discuss the PDUFA, Pre-NDA
meeting, NDA submission process, Refusal to File,
review cycles, advisory committees, final action of
approval and complete action, labeling process, and
post-approval commitments.
XVb
REDEFINING THE CRAMER DECISION TREE FOR THE
SAFETY EVALUATION OF NEW FOOD ADDITIVES.
Timothy B. Adams, The Flavor and Extract
Manufacturers Association, Washington, DC
The 1978 Cramer et. al. Decision Tree (DT) was the
first rigorous attempt to relate chemical structure to
toxic potential. Based upon toxicity and metabolism
data available at the time, it proposed three classes of
toxic potential: Class I, structures suggesting a low
order of oral toxicity; Class II, structures less innocuous
than those in Class I, but having insufficient data to
support placing them in Class I or III; Class III,
structures that permit no presumption of safety or
whose structural features may even suggest increased
toxic potential. More than twenty years later, a toxicity
database was developed to identify intake thresholds
for each DT class (Munro et al., 1996). These
thresholds became part of the larger thinking about
Thresholds of Toxicological Concern (TTC). Based on
the chemical structure, the TTC values provided a
conservative estimate of a chronic oral exposure below
which the substance would not present a significant
toxic potential. Although the use of TTC has expanded
into a number of areas (e.g., indirect food additives,
flavor
chemicals,
genotoxic
impurities
in
pharmaceuticals), no attempt has yet been made to
update the data upon which the DT was developed.
This presentation will focus on the revision of the DT
and its impact on the TTC concept. The DT revision is,
in fact, an expansion of the original DT, based primarily
on the use of current knowledge of metabolism,
structure activity relationships, and toxicity. The
expanded DT will provide the basis for further
subdivision within the DT and, as a consequence, the
development of additional structural classes. The
application of new steps in the expanded DT will be
discussed in the context of the updating of TTC.
XIVd
NONCLINICAL REGULATORY & SAFETY OVERVIEW FOR
NONPRESCRIPTION (OVER THE COUNTER) PRODUCTS
AT THE FDA Wafa A. Harrouk, Ph.D., US FDA, CDER,
OND, ODEIV, Silver Spring, MD
The presentation will focus on the special aspects of OTC approval
processes which include IND/NDA packages, OTC monograph
regulations, and Rx-to-OTC switches. The speaker will discuss key
aspects of the similarities and differences between Rx and OTC
review process, and highlight challenges encountered in developing
a safety recommendation from the regulatory and scientific
perspectives.
XVa
STRUCTURE-BASED THRESHOLD OF TOXICOLOGICAL
CONCERN IN RISK ASSESSMENT
Susan P. Felter,
Procter & Gamble
In the absence of chemical-specific data, TTC
provides a method to determine a conservative
estimate of a chronic oral exposure below which there
is a very low probability of risk. The utility of TTC as a
pragmatic risk assessment tool has been wellestablished and accepted by regulatory bodies in a
number of areas (e.g., indirect food additives, flavor
chemicals, genotoxic impurities in pharmaceuticals).
Another area for which TTC has received extensive
consideration is in the area of cosmetics and personal
and household care products. In extending the
applicability of TTC to these areas, a number of factors
have been considered including the chemical domain
of the databases supporting the TTC exposure limits,
72
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
XVc
APPLICATION OF THE MARGIN-OF-EXPOSURE (MOE)
APPROACH TO FOOD ADDITIVES
Michael J. DiNovi,
US FDA, Riverdale, MD
Global regulatory agencies have long relied on a
safety assessment approach to evaluating new
additives or new uses for additives currently in the
food supply. This approach involves a simple
comparison between an estimate of daily intake (EDI)
and an acceptable daily intake (ADI), which is typically
derived from animal studies. While this approach is
effective for a yes/no system, it does not allow
comparisons between additives. A margin of exposure
approach has been developed for the risk assessment
of contaminants in food (Benford 2010) that can be
broadened for use with food additives. In this
approach, a toxicological point of departure (the
benchmark dose) is determined from observed effect
levels in animal tests. A statistical evaluation of the
dose-response curve allows for the determination of
upper and lower bounds for each dose point.
Commonly, a 5th or 10th percentile of the effect is
evaluated (i.e., the dose where the effect is noted in 5
or 10 percent of the animals tested), with the lower
confidence limit supplying the point of departure. This
point is called the BMDL5 (or 10). The ratio of the
BMDL to the EDI is the margin of exposure, with larger
values indicative of “safer” additives. Examples from
the cited paper and for some commonly used additives
will be shown.
1)
Benford, D., Bolger, P.M., Carthew, P., Coulet,
M., DiNovi, M., Leblanc, J.-C., Renwick, A.G., Setzer,
R.W., Schlatter, J., Smith, B., Slob, W., Williams, G.,
and Wildemann, T. (2010) Application of the Margin
of Exposure (MoE) Approach to Substances in Food
that are Genotoxic and Carcinogenic. Food and
Chemical Toxicology, 48(1):S2-S24.
2011
proposed drugs). In this presentation, the use of
various scenarios and chemoinformatic systems for in
silico analysis of compound safety liabilities will be
discussed. An overview of these approaches, including
their strengths and limitations will be presented.
Validation studies on the predictive accuracy of these
systems for various toxicology endpoints will be
explained as well as how clinical trial data are used to
develop hypothesis-based models. Examples where
chemoinformatic tools have been employed in applied
regulatory research at FDA in order to screen naturally
occurring chemicals found in botanical preparations for
signals of hepatic toxicity will also be presented. Given
that many botanicals and chemical substances within
dietary supplements can in fact be data poor, with
respect to toxicology animal study data, the use of
chemoinformatics may be considered as an alternative
method to animal testing. One of the goals in our
collaboration is to help support safety assessments via
additional predictive evidence to help prioritize
substances for animal testing.
XVe
REGULATORY
USE
OF
COMPUTATIONAL
TOXICOLOGY TOOLS AND DATABASES AT THE
FDA, OFFICE OF FOOD ADDITIVE SAFETY
Kirk Arvidson, Office of Food Additive
Safety, Center for Food Safety and
Applied Nutrition, U.S. Food and Drug
Administration, College Park, MD
Over ten years ago, the U.S. Food and Drug
Administration’s Office of Food Additive Safety (OFAS)
implemented the formal use of structure activity
relationship (SAR) analysis and quantitative structure
activity relationship (QSAR) analysis in the premarket
review of food-contact substances. Currently, OFAS
uses multiple (Q)SAR models in its (Q)SAR evaluations
of food-contact substances and is investigating the use
of metabolism data and metabolism predictive models.
More recently, OFAS has been developing a
sustainable data management and storage system
(Chemical Evaluation and Risk Estimation System
(CERES)), that will provide decision support tools for
both pre-market and post-market safety assessments
of food additives and food-contact substances and
food contamination issues. The development of CERES
will provide a single unified data repository and
analysis system that compiles available information on
a substance, including: chemical structures and
properties, regulatory records, toxicity studies,
biological screening assays, (Q)SAR models and
application programming interfaces (APIs) to
commercial (Q)SAR tools.
In cases where no
information is available for a particular substance,
XVd
CHEMOINFORMATIC APPROACHES FOR TOXICOLOGY
PREDICTIONS
Kevin P. Cross1, Edwin Matthews2,
3 1
Luis G. Valerio, Jr ., Leadscope, Inc. 1393 Dublin Rd,
Columbus, OH 43215, 2Office of Food Additive Safety,
Center for Food Safety and Applied Nutrition, U.S.
Food & Drug Administration, College Park, MD 20740,
3
Science and Research Staff, Office of Pharmaceutical
Science, Center for Drug Evaluation and Research, U.S.
Food and Drug Administration, 10903 New Hampshire
Avenue, Silver Spring, MD 20993
Chemoinformatic (computational) approaches are
comprised of a variety of tools, many of which are
enabled with predictive power to screen and analyze
substances found in a wide range of regulated
products (food additives, dietary supplements,
73
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
CERES provides tools to identify potential safety
concerns by applying mode-of-action-driven (Q)SAR
prediction models and for identification and analysis of
data on structural and biological analogs (read-across).
The presentation will describe the (Q)SAR tools
available at OFAS, the application of (Q)SAR tools to a
real-world example and the future directions of (Q)SAR
within OFAS through the CERES system.
2011
Preclinical assessments of abuse liability are performed
to provide an early indication of a drug’s abuse
potential and can contribute to key strategic decisions
surrounding the development of drug products. The
behavioral assessment of drugs in animals is an
evolving field and a variety of approaches should be
considered when designing studies to assess the abuse
potential of a drug product. Recent dialogue between
representatives of the pharmaceutical industry and the
FDA’s Controlled Substance Staff has provided
guidance regarding best practices when designing
preclinical abuse liability studies. The purpose of this
presentation is to describe the rationale and
procedures for conducting preclinical abuse liability
studies, with a focus on best practices, as discussed
during the 2010 FDA-Industry Dialogue. To this end,
the audience will be introduced to general concepts
and considerations when developing a preclinical
strategy. Following this introduction, the discussion
will focus on the intricacies of key preclinical
behavioral studies including self-administration, drug
discrimination, and withdrawal/dependence studies.
XVIa
SUMMARY OF ISSUES COVERED IN THE FDAINDUSTRY 2010 DIALOGUE SESSION ON THE DRAFT
GUIDANCE ON ASSESSMENT OF ABUSE POTENTIAL OF
DRUGS
Jennie L. Walgren, Ph.D., Eli Lilly and
Company, Indianapolis, IN
Over the past several years there has been an active
effort in both industry and the FDA to openly discuss
and debate approaches to abuse liability assessments
of pharmaceuticals in development. The first FDAIndustry dialogue held in 2008 involved a question and
answer session with FDA’s Controlled Substances Staff
addressing case studies provided by industry
colleagues. Following the release of the draft FDA
guidance on Assessment of Abuse Potential of Drugs in
January 2010 and extensive comments submitted to
the FDA from industry, additional dialogue was
proposed.
A second dialogue session between
industry representatives and FDA staff occurred in
November 2010 where industry colleagues in a crosscompany group posed specific questions and proposals
on topics covered in the draft guidance. These topics
included general/cross-functional issues such as
definitions of terms in the guidance and guidelines for
determining when abuse liability assessments are
required; regulatory/procedural issues in determining
abuse potential; strategy of approach and design of
nonclinical abuse liability studies; evaluation of clinical
trial data, and the design and interpretation of human
abuse potential studies; and risk assessment and risk
management. The presentations in this symposium
will be focused on providing an overview of the topics
highlighted by the industry group and the feedback
that was received in several of these areas, including
nonclinical and clinical abuse liability study designs,
regulatory expectations, and a proposed flow scheme
for nonclinical abuse liability assessments.
XVIc
CLINICAL STUDY DESIGN CONSIDERATIONS
Marta
Sokolowska , Ph.D., Grünenthal USA, Inc., Bedminster,
NJ
Abuse potential of drugs is evaluated based on data
collected throughout the drug development program.
The clinical assessments incorporate analyses of the
human abuse potential study in addition to
examination of adverse events of special interest and
aberrant behaviors observed in Phases I - III. Even
though the FDA Draft Guidance for Industry:
Assessment of Abuse Potential of Drugs (Jan 2010)
clarified some aspects of these assessments, further
gaps have been identified. This presentation will focus
on interactions between the Cross Company Abuse
Liability Consortium and FDA discussing issues
associated with the human abuse potential study
design, impact of various factors on data analysis
including the differentiation between statistically
significant versus clinically important differences.
Additionally, methodology to evaluate adverse events
and aberrant behaviors will be discussed.
XVId
REGULATORY EXPECTATIONS
Beatriz Rocha, MD.,
Ph.D. Worldwide Regulatory Affairs, Merck & Co., Inc.,
Rahway, NJ
On January 2010 FDA published the Draft Guidance
on Assessment of Abuse Potential of Drugs. Key
comments to the Draft Guidance that were proposed
by the Cross Company Abuse Liability Consortium
XVIb
STUDY DESIGN OF ANIMAL BEHAVIOR STUDIES
Kristin Horn, Ph.D., Bristol-Myers Squibb, Mt. Vernon,
IN
Data from abuse liability evaluations are needed to
support New Drug Applications and inform final
scheduling under the Controlled Substances Act.
74
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
(CCALC) were incorporated into many of the individual
company's and PhRMA's submissions to the FDA
docket. During the commenting period the Controlled
Substance Staff of the FDA (CSS), in an attempt to
better understand stakeholder comments on the draft
guidance, approached the CCALC to explore the
possibility of a dialogue session focused on the
guidance. The CCALC/CSS Dialogue Session occurred
on November 2010, and gave origin to an extremely
collaborative discussion towards addressing critical
public health needs and bridging scientific gaps of the
assessment of abuse potential.
This presentation will focus on CCALC's comments
of the regulatory topics included in the FDA Draft
Guidance. Procedural details regarding CSS review
process of the Abuse Potential package included in the
filing of the New Drug Application (NDA), timelines of
the CSS review during the review of the NDA, and
communication with the sponsor are highlighted,
mostly in the context of the frequent gap that occurs
between NDA approval by the FDA and scheduling
recommendation by the DEA, which is in the critical
path for commercialization.
The CSS/CCALC Dialogue Session opened the door
for productive interaction towards the advance of the
science of abuse potential assessment and significantly
contributed towards a solid collaborative relationship
between industry and the FDA.
2011
XVIIa
WHAT’S NEW IN ANIMAL WELFARE AND IN THE NEW
GUIDE? WHERE DID WE COME FROM, WHY ARE WE
HERE, AND WHERE ARE WE GOING?
Patricia V.
Turner, BSc, MSc, DVM, DVSc, DACLAM, DABT,
University of Guelph, Guelph, Canada
A quick review of the philosophy, ethics, and
cultural thinking behind today’s regulations and their
context within our science will set the groundwork for
understanding current developments in the regulatory
environments and the cultural settings that have
created them. The current changes and updates to
the new guide will be emphasized and their relevance
to in vivo toxicology and safety assessment laboratory
settings will be discussed. Emphasis will be on
practical adjustment to the guideline and how
common sense and the new regulations can be
integrated together into a reasonable achievable
successful outcome.
XVIIb
SCIENCE, 3R’S AND EXPERIMENTAL DESIGN….
SHIFTING THE BALANCE WITH NEW TECHNOLOGY
AND BETTER EXPERIMENTAL DESIGNS TO SUPPORT
IMPROVED ANIMAL WELFARE
Henry Holzgrefe,
Scientific Advisor, Navigator Services, Charles River
Laboratories
This talk will present an understanding of the
approaches that can be made with technology while
meeting with 3R’s philosophical directions.
The
emphasis on improved experimental constructs using
better designs, better technology, and improved
measures to enhance statistical power, reduce
animals, and improve outcomes will be emphasized.
Practical suggestions from experience with statistical
perspectives for selecting better designs with
increased study power and improved outcome
planning to yield fewer animals used will be shared
with participants.
XVIe
FLOW CHART HIGHLIGHTING KEY DECISION POINTS IN
PRECLINICAL PROGRESSION
Mary Jeanne Kallman,
Ph.D., Covance Laboratories, Inc., Greenfield, IN
This presentation will provide an update on the
requirements and expectancies for preclinical testing
of new compounds for FDA registration. New insights
gained from the 2010 interaction with the FDA
Controlled Substance Staff will be the primary focus of
the discussion. The evolving dialogue with the
Controlled Substance Staff has focused on the future
expectancies of the agency.
XVIIc
DIRECTIVE 2010/63/EU: THE RENEWED EUROPEAN
FOCUS ON PROTECTION OF ANIMALS USED FOR
SCIENTIFIC PURPOSES AND ITS INFLUENCE ON OUR
RESEARCH
Karen Blumer, Ph.D., Novartis
International AG, Basel, Switzerland
This talk will cover the prior EU regulatory landscape
and will take the attendees forward into understanding
the new directive changes that are now legislated and
moving into EU research laboratories. The role of the
3R’s, the EU cultural context, and details of the
directive will be reviewed in this comparison of the old
and new legislation.
Current legal and ethical
75
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
implications that affect our future scientific in vivo
research environments will be shared.
2011
XVIIId
UPDATE ON ICH M7 GUIDANCE WITH EMPHASIS ON
QSAR AND GENOTOXIC IMPURITIES
Kenneth
Hastings, MPH, DrPH, DABT, Sanofi-Aventis
While commercially available and proprietary
Quantitative Structure-Activity Relationship (QSAR)
programs have long been used by PhRMA companies,
the application to genotoxic impurities (GTI) is the first
instance where these tools are being used in a
regulatory context. The EMA and FDA have published
guidance on identification and control of GTIs in
human drugs and currently an ICH guideline (M7) is
under development. While there is a consensus that
QSAR programs should be used to identify potential
GTIs, the types and number of programs which should
be employed has not been clarified. This presentation
will be given by the acting chair of the PhRMA (Q)SAR
subcommittee who will provide a status update of ICH
M7 and associated discussions around (Q)SAR and
genotoxic impurities.
XVIId
DEPARTMENTAL COOPERATION FOR BETTER SCIENCE
AND BETTER WELFARE: A CASE STUDY
Russell
Bialecki, Ph.D., Astra Zeneca, Wilmington, DE
This case study presents an example and validation
for using a new approach to integrated study designs
that improves scientific outcomes while satisfying
animal welfare goals. Combining the efforts of three
separate corporate research departments (PK/PD,
Metabolism, and Pharmacology), combining several
studies into a single design, and sharing data sets
accomplished several improved outcomes: reduction
of animals, fewer studies, and advancing the
compound over several research hurdles.
XVIIIa
CURRENT STATUS OF BIOSIMILAR LEGISLATION
Barbara J. Mounho, PhD, DABT, Amgen Inc., Thousand
Oaks, CA
Biosimilars are biological products derived from
recombinant DNA technology, which are claimed to be
highly similar to an innovative biological product
(reference product) in terms of quality, efficacy, and
safety. While biosimilars are a relatively new category
of biological therapeutics, interest in the development
and marketing of biosimilars continues to increase in
the pharmaceutical industry as innovator products
reach the end of their patent protection period. The
first formal regulatory pathway for the approval of
biosimilar products was established in 2003/2004 in
the European Union (EU).
Subsequent to the
regulatory guidelines established by the EU, guidelines
for the approval of biosimilar products have been
issued by the World Health Organization (WHO) as well
as in numerous regions around the world, such as
Japan and Canada. This presentation will provide a
high level review of the approaches of the WHO and
regulatory authorities in various key regions in the
world, as well as review some of the issues relating to
the approval of biosimilars.
76
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
POSTER ABSTRACTS
P100
ENHANCEMENT OF URINE SAMPLES FROM MICE
Anthony Rohr, BS, LATG, Nichole James, BS, LATG,
Erin Warren, AAS, MLT (ASCP), Ty Schoenborn, BS,
LAT, Lacey Ciaravino, Thomas Dailey, BS, ALAT, Jan
VanSteenhouse, DVM, PhD, DACVP
Historically, all animals had been fasted prior to
blood and urine collections for toxicology studies.
Because of the mouse’s propensity to not drink if not
fed, this often resulted in varying degrees of
dehydration and low blood and urine volumes.
Thus, fasting was abandoned for mice with resultant
dramatic improvements in obtainable blood volumes
with no detrimental interpretive effect on other
hematology or clinical chemistry parameters.
However, the usable volume and quality of urine
samples remained a quality issue. Urine samples in
the past and until recently were collected via
dripping into an open container positioned below
the cage allowing for considerable evaporation. In
spite of mesh filters over the outflow collection tube,
urine samples tended to be flocculent with varying
amounts of diet debris contamination.
We have developed a method by which a
gelatinous form of food is offered to mice during
urine collection to eliminate the contamination
issues and the physical collection device has been
modified to mitigate the potential for evaporation.
Two internal studies were conducted using the
newly created protocol for urine collection in mice.
These studies demonstrated clear advantages of this
procedure over the previous protocol for collecting
urine from mice.
The number of samples that met the minimum
volume requirements for analysis using the Clinitek
Atlas® Automated Urine Chemistry Analyzer were
increased by 56%. In addition, the quality of the
urine was also enhanced as evidenced by the
analysis of the data produced by the Clinitek Atlas®
and the drastic reduction of foreign sediments in the
microscopic evaluation. There were no physiological
or toxicologically meaningful differences relative to
the different diets that would affect interpretation
of hematology or clinical chemistry results. MPI
Research has adopted this as our standard protocol
for urine collection in mice.
77
POSTER
ABSTRACTS
P101
PHARMACOKINETIC EVALUATION OF DILTIAZEM
COMPARING MANUALLY-SPOTTED DRIED BLOOD
SPOTS (DBS) WITH AUTOMATED DRIED BLOOD
SPOTS, AND PLASMA SAMPLES, COLLECTED BY THE
CULEX® AUTOMATED SAMPLING SYSTEM Bradley
Gien, Peter White, Robin Lane, Tyler DeGraw,
Bhavna Mistry, Amanda Plumb, John Maltas, and
David Hopper, BAS Inc. 2701 Kent Avenue, West
Lafayette, IN 47906
Dried blood spot (DBS) sample collection has
many advantages compared with traditional
sampling
techniques.
Here
we
describe
pharmacokinetic evaluation of a single dose of
diltiazem (DTZ) comparing use of a novel automated
DBS technique to manually spotted DBS, and
traditional plasma samples, all collected using the
Culex® Automated Blood Sampling system (ABS).
One group of 8 male rats was prepared with intraarterial catheters in both femoral and carotid
arteries externalized for connection to the ABS. The
rats were administered DTZ by oral gavage, at a
dose of 20 mg/kg. Blood samples were collected at
0, 0.25, 0.5, 1, 2, 3, 4, 6, and 8 hours post dose. The
ABS was successfully used to robotically collect
whole blood samples in the DBS format in support of
a rat pharmacokinetic study. Exposure profiles were
similar when measured in plasma, ABS-spotted DBS,
or manually pipetted DBS. Differences in the mean
AUC0-8 and CMAX between manually and Culex
collected DBS were <14.0%. Lowest AUC0-8 and CMAX
variability was observed with automated DBS (39.0 /
40.0% CV respectively). Blood collected before and
after the sampling schedule indicated some decrease
in red cell mass from the intensive bleeding
schedule, but post-study results remained within the
laboratory reference range (RBC) or slightly lower
(Hgb and HCT). Manually-spotted DBS were more
variable in size, shape and appearance than
automated DBS. Labor required for manual spotting,
and for traditional plasma processing, was greater
than for automated DBS. Sample shipment was
easier and less costly for DBS cards vs. frozen
plasma.
100 series – Methodology
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P102
THE EYES HAVE IT: CALF VERSUS ADULT EYES IN THE
BOVINE CORNEAL OPACITY AND PERMEABILITY
(BCOP) ASSAY. Donahue, DA1, Hall, D2, Cerven D2,
DeGeorge, G2, and Avalos, J1.
1-Kao Brands
Company, Cincinnati, OH.
2-MB Research
Laboratories, Spinnerstown, PA.
The Bovine Corneal Opacity and Permeability
(BCOP) assay uses excised bovine corneas obtained
from cattle slaughtered for food use. Consequently,
the age of the cattle is generally not provided with
the corneas. This introduces a variable at the start
of the assay, which can be reduced by using eyes
from cattle at a defined age.
The OECD guidelines
for the testing of Chemicals No. 437 recommends
the use of eyes from cattle 6 to 12 months of age but
encourages investigators to report the estimated age
and/or weight of the animals providing the corneas.
In a commercial operation, capable of killing large
numbers of cattle to provide suitable numbers of
eyes, it may not be possible to determine age and
weight since animals are received from a number of
suppliers.
Additionally, random-source animals
typically have not been raised in constant
environment and are subject to numerous
environmental variables. This study looked at the
effect of the cattle’s age on the BCOP assay.
The
calf eyes used in this study were obtained from a
well-managed barn-raised herd, which had weekly
veterinary monitoring and controlled feed and
medication.In this study we compared the In Vitro
Scores (IVS) from random source cattle corneas with
those of corneas from a well-managed calf herd of 4
to 5 months of age. Thirty over the counter
cleaners, hair dyes, hair sprays, deodorants and
moisturizers, which had IVS scores obtained from
random-age animals were used in the evaluation.
The IVS scores from the random aged animals
ranged from -0.62 to 111.58. The IVS scores from
age-defined calf eye corneas ranged from -1.11 to
22.86.
MORE PREDICTIVE IN VITRO ASSAYS .
2011
ONE MODEL IN MORE
COMMON USE IS RECONSTITUTED HUMAN EPIDERMIS
(MATTEK E PIDERM) RESEMBLING IN VIVO HUMAN SKIN. IN
THIS INVESTIGATION , THESE HUMAN SKIN MODELS WERE
EXPOSED
TO
A
KNOWN
SKIN
IRRITANT ,
8METHOXYPSORALEN (8MOP), AT A DOSE COMPARABLE TO
THE EC10. THE SAMPLES WERE ALSO EITHER KEPT IN THE
DARK OR EXPOSED TO SOLAR SIMULATED LIGHT (SSL). GENE
ACTIVITY WAS ANALYZED WITH MRNA MICROARRAYS AT 1,
6, AND 20 HR TO DETERMINE POTENTIAL CELLULAR AND
MOLECULAR MECHANISMS OF ACTION . TWO LEVELS OF
BIOLOGICAL CONTROL SAMPLES WERE USED : A ) SAMPLES
NOT TREATED WITH 8MOP AND KEPT IN THE DARK OR
EXPOSED TO UV LIGHT AND B ) SAMPLES TREATED WITH
SODIUM DODECYL SULFATE (SDS) [POSITIVE CONTROL ].
PURIFIED, LABELED, AND FRACTIONATED C RNA ISOLATED
FROM EACH OF THE BIOLOGICAL SAMPLES WERE HYBRIDIZED
ONTO
WHOLE
HUMAN
GENOME
M RNA
EXPRESSION
MICROARRAYS , EACH CONTAINING 41,000 UNIQUE PROBES .
DATA ANALYSIS WAS DONE BY A TIERED APPROACH .
COEFFICIENTS OF VARIATION (CV) FROM ALL THE PROBES
PASSING QUALITY MEASURES OR A TOTAL OF 11,335
PROBES FOR EACH BIOLOGICAL SAMPLE WITHIN THE
TREATMENT GROUPS RANGED FROM
18.5-33.1%. THE
LEAST VARIABILITY WAS OBSERVED WITH THE PRINCIPAL
(PCA) FOR THE NEGATIVE CONTROL
(THOSE NOT EXPOSED TO 8MOP) AND THE
SAMPLES EXPOSED TO 8MOP UNDER DARK CONDITIONS .
THE MOST ACTIVITY WAS SEEN WITH 8MOP AND SSL
EXPOSURES AT 6 AND 20 HR AS WELL AS EXPOSURES TO
SDS, THE POSITIVE CONTROL. SEVERAL GENES IN COMMON
BETWEEN TREATMENTS WITH SDS AND 8MOP WERE
CXCL14, FIBRILLIN 2, TROPOMYOSIN ALPHA 1, CYP26B1,
HSP70B AND VEGF-A. FUNDING WAS PROVIDED BY
NIEHS GRANT NO. 5-R44-ES-11927-02.
COMPONENTS ANALYSIS
SAMPLES
P104
VEHICLE-DEPENDENT
EFFECTS
ON
HEXYLCINNAMAL-DEHYDE RESPONSES IN THE LLNA.
G. L. DeGeorge, M. Carathers, J. Tao, D. R. Cerven.
MB Research Laboratories, Spinnerstown, PA.
Hexylcinnamaldehyde (HCA) is the default,
preferred positive control substance in the Local
Lymph Node Assay (LLNA), due to its moderately
potent dermal sensitizing properties. We have
tested the effects of use of varying vehicle solvents
for HCA on the endpoints of Stimulation Index (SI),
lymphotype subsets (immunophenotyping; IP), and
irritation as measured by ear swelling. Herein, we
show that the choice of vehicle does biologically and
statistically significantly (P>0.05) impact the HCA
endpoint values, most importantly, the SI. HCA at
25% was evaluated in all vehicles (AOO, DMSO,
Acetone, Ethanol and DAE433, petrolatum, PG, etc.),
P103
GENE EXPRESSION PROFILING OF AN IN VITRO
HUMAN SKIN MODEL AFTER PSORALEN PLUS
ULTRAVIOLET LIGHT-INDUCED PHOTOTOXICITY.
Pratt, Lisa F.1; DeGeorge, George L.1; Cunningham,
Mary Jane2.
1. MB Research Laboratories,
Spinnerstown, PA. 2. Nanomics Biosciences, Inc.,
Cary, NC.
T O REDUCE THE NUMBER OF ANIMALS FOR SAFETY
SCREENING OF POTENTIAL IRRITATING CHEMICALS AND
PHOTOTOXINS , EFFORTS HAVE BEEN MADE TO DEVELOP
78
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
and compared to naïve or untreated controls, as
appropriate.
Most importantly, some vehicles
(besides the default AOO) that are commonly used
were more prone to causing or enhancing irritation
induced by vehicle-alone treatment, or either
decreased or increased SI values and variability
when compared to AOO. Generally, DAE433 was a
‘better’ vehicle than DMSO alone, resulting in lower
background proliferation and less irritation (ear
swelling Day 1 through Day 6). Petrolatum gave
good results as a vehicle for 25% HCA with an
SI=10.3, comparable to AOO SI=9.8 and DMF SI=9.9.
Acetone and PEG had significantly higher SI values
and B:T cell ratios than DMSO and AOO. DMSO and
DMA had the lowest SI values for 25% HCA, at 7.8
and 5.8, respectively. In addition, DMSO was
significantly irritating to the ears of mice as a vehicle,
and caused very pronounced ear swelling when used
as a vehicle for HCA (>15% increase). In conclusion,
the vehicle chosen for the LLNA can significantly
affect multiple endpoints of interest in the assay,
especially the Stimulation Index, and that this
variability should be taken into account when testing
similar or borderline test substances in vehicles
other than AOO.
P106
DEVELOPMENT OF THE REPLACEMENT OCULAR
BATTERY-ROBATT - TIERED TESTING STRATEGY OF
ALTERNATIVE TOXICOLOGY TESTS TO REPLACE THE
NEED FOR RABBIT EYE TESTS.
Cerven, D., Piehl,
M., DeGeorge, G. MB Research Laboratories,
Spinnerstown, PA 18968
Using a series of non-animals assays in a tiered
approach, the Replacement Ocular Battery (ROBatt)
accurately predicts the categories of acute ocular
irritation corresponding to OECD, EPA and GHS
guidelines.
At present, no single alternative assay has been
accepted by regulatory agencies to completely
replace the use of live animals. The BCOP (Bovine
Cornea Opacity/Permeability) test has been
accepted by OECD as a screen for severe and
corrosive
materials.
The
Cytosensor
Microphysiometer has been accepted for sub-severe
testing but it applicable for aqueous-based
materials. The ROBatt approach uses a series of two
to three non-animal assays to categorize both
aqueous and non-aqueous materials.
An NIH/FDA Grant has been awarded to develop
the ROBatt decision tree criteria. Initially screening
will use the Chorioallantoic Membrane Vascular
Assay (CAMVA) to discriminate slight or non-irritants
from moderate to severe irritants. Slight or nonirritating materials will be categorized using the
Porcine Cornea Confocal Assay (PorFocal). The
Bovine Cornea Opacity/Permeability test (BCOP) will
be used for discriminating between moderate and
severe to corrosive materials and the Porcine Cornea
Opacity Reversibility Assay (PorCORA) will be used to
categorize severe irritants and corrosives.
Fifty validation chemicals from the ECETOC database
of ocular irritation will be initially used. Having
performed over 6,700 CAMVA, 5,700 BCOPs, and
nearly 100 PorCORA assays, the researchers are
confident of the ability to complete categorize any
material to international standards.
P105
IRRITATION IN THE LLNA: 2000 MICE EAR
THICKNESS MEASUREMENTS DEPENDENCE ON
VEHICLE AND HCA TREATMENT.
DeGeorge,
George L., Carathers, Micheal R.; Cerven, Daniel R..
MB Research Laboratories, Spinnerstown, PA.
THE LOCAL LYMPH NODE ASSAY (LLNA) IS KNOWN TO BE
SUSCEPTIBLE TO FALSE -POSITIVES CAUSED BY IRRITATING
TEST SUBSTANCES . W E HAVE INCORPORATED EAR THICKNESS
MEASUREMENTS ON DAYS 1, 3 AND 6 OF THE LLNA IN
ORDER TO MEASURE DERMAL IRRITATION -INDUCED EAR
SWELLING . KNOWN LLNA FALSE-POSITIVE IRRITANTS SLS
AND BAC CAUSED INCREASES IN EAR SWELLING ON DAY 6
(WHEN COMPARED TO DAY 1) OF 25% OR GREATER
(>1.25-FOLD). I N ADDITION, THE DEFAULT POSITIVE
CONTROL H EXYLCINNAMALDEHYDE (HCA) HAS IRRITATION
POTENTIAL , WHICH WAS CONFIRMED AT CONCENTRATIONS
ABOVE 10% HCA. I NTERESTINGLY , ALL COMMON LLNA
VEHICLES (ACETONE :O LIVE O IL 4:1(AOO), ACETONE ,
E THANOL, DIMETHYLACETAMIDE :ACETONE :E THANOL 4:3:3
(DAE433), ETC.) DID NOT AFFECT EAR SWELLING THROUGH
DAY 6, WITH THE NOTABLE EXCEPTION OF
DIMETHYLSULFOXIDE (DMSO). DMSO-TREATED MOUSE
EAR SWELLING WAS INCREASED OVER 15% DURING THE SIX DAY EXPERIMENTAL TERM. THIS IMPLICATES DMSO AS
P107
COMPARATIVE
STUDY
OF
PLASMA
MICROSAMPLING IN MALE RATS AFTER A SINGLEDOSE OF ACETAMINOPHEN Alan Stokes1, Tammy
Moose1, Carie Kimbrough2, Mark Mullin3, Jim
Kenney4, Joe Siple4, Neil Spooner5 1 Safety
Assessment, GlaxoSmithKline, Research Triangle
Park, NC, USA, 2 Statistical Sciences, GlaxoSmithKline,
Research Triangle Park, NC, USA, 3 Bioanalytical
Sciences and Toxicokinetics, GlaxoSmithKline,
Research Triangle Park, NC, USA, 4 Drummond
Scientific Company, Broomall, PA, USA, 5
MODERATELY IRRITATING AND POSSIBLY A PROBLEMATIC
VEHICLE FOR THE
LLNA.
79
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Bioanalytical
Sciences
and
Toxicokinetics,
GlaxoSmithKline, Ware, UK
Total blood volumes in animals, especially
rodents, present a practical limitation when
sampling blood over a 24 hour period to obtain
toxicokinetic data. This limitation can increase the
numbers of rats or mice used on a study and/or limit
the number of samples collected per animal.
Microsampling strategies (e.g., dried bloodspots) are
one way to overcome this limitation and have
become more common in recent years due to the
increased pressure on the pharmaceutical industry
to reduce animal use and costs. Reducing the
volume of blood collected at each time point can
have a positive impact by decreasing the number of
animals used on a study and allowing for more
robust serial sampling in an individual animal.
Plasma microsampling (~75 L of blood per time
point) significantly decreases the amount of blood
(~70%) collected per time point for toxicokinetic
analysis. Using EDTA coated capillary tubes with a
thixotropic agent, it is possible to decrease the
volume of blood collected for plasma exposure
analysis. The current study compared data collected
in male rats (n = 8) after a single 600 mg/kg dose of
acetaminophen using a plasma microsampling
method and a standardized plasma collection
method (250 L of blood per time point). Drug
exposure at 4 separate time points (1, 2, 5, and 8
hours) were compared and found to be within 8%
overall and within 5% for the majority of samples (23
of 32). Mean AUC and Cmax values were within 1% of
each other using the 2 different collection methods
with individual AUC or Cmax values within 5% or 6% of
each other, respectively.
‘social ranking’ behavior when group housed.
However, there are several advantages to consider
with the inclusion of male mice in LLNA testing
including a more refined and responsible use of
animals from supplier breeding programmes. The
NIH publication highlights that if males are to be
considered, systematic studies evaluating potential
sex differences should be conducted. Therefore, to
begin to systematically assess the appropriateness of
using male mice in the LLNA a comparative guideline
study was conducted with individually housed mice
using
the
well
known
sensitizer,
αHexylcinnamaldehyde (HCA). The study compared 5
male and 5 female CBA/J mice/group, at three test
material concentrations (3%, 10% and 30% (w/v)
HCA), with 1 % aqueous (v/v) pluronic L92 surfactant
as the vehicle. Stimulation indices (SI) for the three
HCA treatment groups were 3.75, 5.59 and 12.50 for
male and 2.19, 4.05 and 7.37 for females,
respectively. The results revealed no significant
difference between samples means or variability
between the sexes and the SI values observed for both
male and female mice were within the range of
historical control data for female mice. EC3 value for
male could not be calculated; however EC3 value for
female (6.05%) was in range of reported value (4.9
to 15%) in guideline. These data provide initial support
for the use of male mice in the LLNA and will be
followed by further experimentation with a variety of
chemicals to systematically evaluate potential for sex
differences in an effort to support the use of male
mice in the LLNA as a further assay refinement.
P109
PRECLINICAL EVALUATION OF A DOCETAXEL
FORMULATION.
Lorraine Webster, John Risvanis,
and Darryl Whittaker. Hospira Australia Pty Ltd,
Melbourne, Australia.
Background: Hospira has developed a stable onevial presentation of docetaxel, a cytotoxic antimitotic drug.
Docetaxel has very low water
solubility, and its delivery in the infusion solution is
achieved by micelle formation in polysorbate 80
(PS80). Hospira Docetaxel contains the same amount
of PS80 as the innovator, with additional excipients
to permit a stable, ready-to-dilute product. Aim: A
preclinical program was designed to confirm that the
changes in the excipients would not alter the in vivo
pharmacology of docetaxel. Methods and Results:
All studies compared Hospira Docetaxel with a then
marketed product and all methods were validated.
Some studies were GLP. The drug released from
micelles in the infusion solution was similar. At
clinically relevant plasma concentrations (0.2 to 2.0
P108
EVALUATION OF SEX SENSITIVITY IN LOCAL
LYMPH NODE ASSAY
T IWARI V.K., D ALAL V.,
V ERMA R. D UBEY V., M ANISH R., P ANDEY S., P ATEL
R, B RAHMANKAR M. B OVERHOF , D. * AND W OOLHISER
M.*
(J AI R ESEARCH F OUNDATION , V ALVADA 396
108, G UJARAT , I NDIA ) *TERC, T HE D OW C HEMICAL
C OMPANY , M IDLAND , MI, USA
The current OECD Test Guideline for the conduct
of the Local Lymph Node Assay (LLNA) recommends
the use of only female mice for the assessment of
skin sensitization potential for a given chemical. The
NIH publication no. 99-4494 recommends that only
female CBA mice be used, as they reportedly
develop a stronger contact dermatitis response
when compared to males. Males were also reported
to display a larger variation in response due to a
greater tendency to fight and to be involved in
80
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
mcg/mL), protein binding by equilibrium dialysis was
similar in dog and human plasma. The immunogenic
potential was also equivalent, as measured by
complement terminal complex (SC5b-9) formation in
10 human serum samples.
A cross-over
pharmacokinetic study was performed in 10 male
Beagle dogs at 1 mg/kg. Where neutropenia was
noted, all animals had recovered prior to the second
dose. Docetaxel was quantitated by a validated
LC/MS/MS method, and plasma protein binding was
determined
using
equilibrium
dialysis.
Pharmacokinetics of total and unbound docetaxel
were equivalent between the two products.
Conclusion: These preclinical studies formed the
basis of assuring that the in vivo pharmacology of a
non-aqueous formulation of docetaxel was
comparable to a then marketed product. Hospira
Docetaxel has been granted marketing approval in
many countries.
subcutaneous injection in rats and this poster will
describe the different trials used to determine the
best technique for administration.
Several
techniques were employed to determine the ideal
method to deliver the test article formulation in the
subcutaneous space consistently and accurately that
would result in predictable and repeatable results.
The technique used on study involved “tenting” the
skin with the injection taking place perpendicular to
the animal.
P111
TAPE STRIPPING REPETITIONS REDUCE THE
STRATUM CORNEUM INVERSELY IN YUCATAN
MINIATURE SWINE
Horlen KP, Brown L, Hanks C,
Liu J, Bouchard GF, Sinclair Research Center, LLC
Miniature swine are a recognized predictive
model for human drug candidate dermatopharmacology studies. Tape stripping is a simple
and effective method for removing the stratum
corneum (SC) and is commonly employed during in
vivo studies investigating the percutaneous
penetration and disposition of topically applied
candidate drugs. The objective of this study was to
assess the remaining thickness of the SC following 0,
10, 20, 30, 40, and 50 repetitions of tape stripping of
skin. Animals were young adult, male Yucatan
miniature swine weighing 33-36kg (N=3). Animals
were maintained under general anesthesia for the
entire duration of the procedures.
Following
clipping of the pelage over the dorsal lumbar and
thoracic areas, 6 sites, approximately 5cm by 5cm,
were demarcated and skin was stripped using U-Line
1.8mm clear acrylic adhesive tape applied with
uniform, firm pressure. Following tape applications,
the center of the each test area was punch biopsied
(8mm) and samples fixed in 10% neutral buffered
formalin. Samples were processed, stained by H&E,
and read under light microscopy. The results
showed an inverse pattern to the number of tape
stripping repetitions. Fifty passes were required to
remove nearly all SC. These data demonstrate that
skin can be stripped of SC in a linear fashion based
upon repetition of the technique.
P110
NEEDLE-FREE INJECTIONS VIA THE SUBCUTANEOUS
ROUTE IN RATS USING THE BIOJECT DEVICE (AN
ALTERNATIVE TO DOSING PRE-CLINICAL SPECIES)
S. Hadd1, G. Ruppert1,R. Stout2, D. Hargreaves1, C.
Coffey1, S. Frantz1 1MPI Research, Mattawan,
Michigan, 2Bioject, Tualatin, Oregon
The industry standard for subcutaneous and other
parenteral routes of drug administration has
historically involved the use of a needle and syringe
system. However, there are many drawbacks to
needle usage in pre-clinical and clinical settings such
as: passage of infectious diseases, potential fear of
needles, and accidental needle sticks. Alternatively,
needle-free injection systems (NFIS) provide an
empowering technology that work by forcing liquid
medications at high speed through a tiny orifice held
against the skin. This creates a fine stream of highpressure fluid penetrating the skin and depositing
medication in the tissue beneath in a fraction of a
second. The novel technology of NFIS has been used
recently in pre-clinical and clinical research but has
not been previously used in rodents via all routes of
injection:
intradermal,
intramuscular,
and
subcutaneous.
In a recent two-phase study conducted to
evaluate and characterize the acute toxicity and
estimate the maximum tolerated dose following a
single subcutaneous dose, and evaluate the toxicity
and toxicokinetics of the test article following 7 days
of repeat subcutaneous dosing in CD® [Crl:CD®(SD)]
rats, NFIS was used as an alternative to the
traditional needle and syringe system. The Bioject®
device had not been previously used for
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P112
GUIDANCE ON THE DERIVATION OF ACCEPTABLE
DAILY
EXPOSURE
(ADE)
VALUES
FOR
PHARMACEUTICALS – AN INDUSTRY PROPOSAL T.
Pfister, and A. Flueckiger. Safety, Security, Health &
Environmental Protection. F. Hoffmann-La Roche,
Basel, Switzerland
The Acceptable Daily Exposure (ADE) concept
follows a well-established paradigm that has long
been successfully used in nutritional toxicology to
set acceptable levels of chemical food contamination
(oral intake) and in occupational toxicology to derive
acceptable levels of workplace exposure (via
inhalation). ADEs are now being introduced as a
measure of safe residual contamination of “multiproduct” manufacturing equipment. Therefore, they
will become the object of new regulatory scrutiny.
ADE is defined as a substance-specific dose that is
unlikely to cause an adverse health event or
undesirable physiological effect if an individual is
exposed daily at or below this dose during lifetime.
The ADE is typically based on nonclinical and clinical
data. Here we propose a standard procedure for ADE
setting from nonclinical safety data: The reference
effect level (e.g. NOAEL) established in the most
sensitive species is multiplied with a human body
weight of 60 kg. The resulting dose has to be divided
by adjustment factors to compensate for
uncertainties in the model applied. These include
interindividual
variability
(F1),
interspecies
differences (F2), duration of the toxicity study (F3),
severity of toxicity (F4), and the quality of the
reference effect level (F5). While default values for
F1 - F5 are provided, we recommend replacing them
by substance-specific values wherever possible.
Modifications of this standard procedure are
proposed for CMR substances. Limitations of the
proposed procedure, different routes of exposure,
and differential sensitivity in human subpopulations
are discussed. In conclusion, we are presenting a
standard approach implemented at F. Hoffmann-La
Roche for the derivation of ADEs which may provide
some guidance for also other toxicologists in charge
of ADE setting.
vertebrate animal testing shall be avoided and/or
minimized through the development of read-across
strategies and the identification of acceptable
surrogates. The relevance of the approach must be
substantiated however through a robust evaluation
of the physicochemical properties and available
toxicological parameters.
This case study, the application of read-across to
fulfill physicochemical and toxicological parameters
in the REACH registration of 2,6-xylenol (2,6dimethylphenol), presents the rationale for the use
of the structural analogues chosen. Various options
including read-across to mixed xylenol isomers or to
specific isomers sharing similar functional groups
were critically evaluated. Consideration was given to
the presence of the phenolic hydroxyl group and the
position of methyl groups as well as data availability.
The predicted metabolic pathways for the
substances chosen were broadly similar based on
similar reactions considering probable and plausible
transformations. A matrix of available REACH Annex
VII and VIII human health toxicity data including the
oral and dermal acute toxicity, skin and eye
irritation, mutagenicity, and repeat dose data were
evaluated to determine the appropriateness of the
approach for extrapolation to higher-tiered study
requirements.
The overall strategy required a well-documented,
well-defined methodical approach for submission
under the regulatory framework. A substance
registration was developed using the read across
approach that defines the impact and importance of
the substance categories, while including other
options such as data waivers. An overview of the
strategy, matrix, hazard analysis and overall risk
assessment will be presented.
P114
THE IN VITRO 3T3 NEUTRAL RED UPTAKE
PHOTOTOXICITY TEST: HISTORICAL CONTROL DATA
DEMONSTRATE REPRODUCIBILITY WITH MULTIPLE
TEST SUBSTANCES AND DIFFERENT IRRADIATION
CONDITIONS.
M. Schwartz1,D. Learn1, M.
1
1
Arocena , A. Brower , M. Brennan1, A. Hoberman1
1
Preclinical Services, Charles River Laboratories,
Horsham PA
The 3T3 NRU Phototoxicity Test historical control
data demonstrates a robust and reproducible assay
in this laboratory. Chlorpromazine (CPZ) as the
positive control for 60 plus sponsored assays
displays reproducibility and assay validation as per
the OECD 432 guideline. The overall IC50 (irradiated)
and IC50 (non-irradiated) was 1.037±0.403 mg/L and
29.198 ±12.053 mg/L, respectively, agreeing with the
P113
IDENTIFYING
APPROPRIATE
READ-ACROSS
SURROGATES IN THE REACH REGISTRATION OF 2,6
XYLENOL
Sanders, M; ARCADIS-US, Waites, R;
SABIC
As part of an integrated testing strategy under the
Registration, Evaluation, and Authorisation of
Chemicals (REACH) regulation, the European
Chemicals Agency (ECHA) has specified that
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
OECD guideline requirements. We have also run
assays using different light sources, UVA/UVB
irradiance ratios and the number of dosed wells per
concentration. In all cases the data are reproducible
and within guidance limits. Evaluation of test articles
with the 96 well plate lids removed, increases the
UVB portion of the irradiance from approximately 19
mJ/cm2 to approximately 32 mJ/cm2 concomitant
with the recommended 5 J/cm2 of UVA irradiance.
The resulting IC50, PIF, and MPE data show no
adverse effect on the assay from the increased UVB
fluence and acceptable CPZ results, allowing
evaluation of test articles absorbing primarily in the
UVB. Cell sensitivity to UVR and cell viability met the
recommended levels, regardless of the UVR
exposure conditions. The dosing of a single well per
test article concentration, as opposed to the typical
dosing of six wells per test article concentration,
generates usable and valid data and increases the
throughput of the assay in a ‘screening mode’. The
3T3 NRU Phototoxicity assay has proven to be a
useful, robust and valid hazard assessment tool in
the preclinical process of drug discovery, either
under standard or other conditions of use.
from Groups 1 (control), 2, and 3 on Days 2
(approximately 2 hours following the mock 24-hour
TK collection in Groups 2 and 3), and then in the
mornings of Day 3, 4, 5 and 8 (5 rats/group).
In Group 2 rats, there were no noteworthy
hematology changes. In Group 3 rats, there were
statistically (P <0.05) and physiologically significant
decreases in red blood cell-associated parameters
(red blood cell counts, hemoglobin concentrations
and/or hematocrit values) compared to pretest and
control values beginning on Day 2 with a
compensatory increase in reticulocyte counts
(notably “high” RNA reticulocytes) observable by
Day 4. Red blood cell parameters were subsequently
increased towards control/pretest range by Day 5
following the TK blood sampling. The results from
this study demonstrate a temporal effect of sparse
TK blood sampling on hematology parameters over a
4-day necropsy interval that is influenced by the
number of TK blood samples collected relative to
necropsy. These effects, which could confound
interpretability of test item-related hematology
changes, should be considered when designing
nonclinical safety studies in rats.
P115
QUANTITATIVE
CHARACTERIZATION
OF
HEMATOLOGY EFFECTS FOLLOWING SPARSE BLOOD
SAMPLING IN RATS:
CONSIDERATIONS FOR
NONCLINICAL STUDY DESIGN.
C.R. Mattis,
P.Katavolos, D.J. Desmond, J.C. Kinney, R.L. Yeager,
L.A. Gallenberg. Global Pharmaceutical Research
and Development, Abbott Laboratories, Abbott Park,
IL 60064.
Assessment of toxicokinetics (TK) using “sparse”
blood sampling in main study rats instead of a
separate satellite cohort provides an opportunity to
reduce the number of rats required to conduct
nonclinical safety studies. In this approach, the
volume and/or number of TK blood samples
collected from each rat are typically reduced in an
attempt to minimize potential blood withdrawal
effects on clinical pathology data, particularly
hematological parameters. The objective of the
present study was to evaluate how a sparse TK blood
collection approach prior to a multiday necropsy
interval affects hematology parameters. Seventyfive female Crl:CD (SD) rats, 11 weeks old and
weighing 192-230g each, were assigned to 3 groups
(Groups 1-3; 25 rats/group). Blood samples (0.375
ml each) were collected via the lateral tail vein on
Day 1 (Group 3 rats) and Day 2 (Group 2 and Group 3
rats) to mimic 6 and 24 hour TK blood sampling,
respectively. Terminal samples were then collected
P116
NEW MODEL OF NONCLINICAL CARDIAC RISK
ASSESSMENT.
Kramer JK1, Myatt, GJ.2; Obejero1,
Paz, C. Breuning-Wright, A.1 Brown AM. 1ChanTest
Corp., Cleveland, OH, USA. 2Leadscope Inc.,
Columbus, OH, USA
Drug-induced inhibition of the cardiac hERG
potassium channel is assumed to predict delayed
cardiac repolarization (DR). The consequent QTc
prolongation is a surrogate marker of torsade de
pointes (TdP), a rare but potentially lethal iatrogenic
outcome. Drugs with effective therapeutic plasma
concentrations (ETPC) within 30-fold of their hERG
IC50s are thought to be dangerous despite the fact
that multiple ion channel effects (MICE) can mitigate
DR. Here we demonstrate that a logistic regression
model, which integrates MICE, predicts TdP with
much greater certainty than the hERG safety ratio
(hERG IC50/ETPC) alone. Safety ratios were calculated
for 40 drugs (19 +TdP and 21 -TdP) from multiple
classes by dividing their hERG, Nav1.5 and Cav1.2
IC50 values by each drug’s ETPC. Two logistic
regression models were constructed; one using the
hERG IC50/ETPC ratio alone (Model 1), the other
integrating hERG IC50/ETPC + Nav1.5 IC50/ETPC +
Cav1.2 IC50/ETPC data (Model 2). The predictive
power of each model was evaluated by performing
leave-one-out cross validations. Each model’s
accuracy for discriminating +TdP and -TdP drugs was
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
determined by comparing their receiver–operator
characteristics (ROC, true vs. false positive rates).
Model 1 had a 52% False Positive Rate associated
with a 90% True Positive Rate and a ROC area under
the curve (AUC) of 0.72. Model 2 significantly
improved accuracy showing a 15% False Positive
Rate associated with a 90% True Positive Rate and a
ROC AUC of 0.86. We propose that models that
incorporate quantitative drug effects on multiple
cardiac ion channels will be robust nonclinical
predictors of cardiac risk.
not at 48 hours, which suggests a potential
metabolite dependent cell cycle block that recovers
after reactive species dissipate. Another interesting
observation was HSP70/72 induction in HepG2 cells
dosed with low concentrations of Geldanamycin,
which is known to cause cellular stress in vivo and
induce HSP proteins. This raises the possibility that
evaluation of drug induced elevation of HSP70/72 in
human liver cells could serve as an earlier indicator
of cellular changes that may be relevant could be
toxicity. These results indicate that multiplexing of
markers directly linked to cellular mechanisms of
toxicity is useful for evaluation of the ability of test
compounds to cause toxicity to isolated liver-derived
cells in vitro. To determine the value of this
approach for prediction of DILI in vivo, it will be
important to undertake a follow up evaluation of a
broad range of marketed drugs which cause DILI or
do not cause DILI in man.
P117
IN VITRO MULTIPARAMETER HEPATOTOXICITY
ASSAY DEVELOPMENT IN HUMAN PRIMARY
HEPATOCYTES AND HEPG2 CELLS WITH S9 LIVER
1
FRACTIONS
Marcoe, KF; Garside, HJ2; Chesnut1
Speelman, J ; Foster, AF2; Ovechkina, Y1; Warrior, U; 1
1
Kenna, JG2; Bowes, J2; O’Day, C1
Ricerca
Biosciences, Bothell, USA and 2AstraZeneca Safety
Assessment UK, Innovative Medicines, Alderley Park,
UK
Drug-induced liver injury (DILI) remains a major
cause of failed drug development and withdrawal of
drugs post marketing.
Therefore predictive
toxicology screening assays are required which
enable early identification and deselection of
compounds that have the potential to cause DILI in
man. In this study, multiplexed high content
screening (HCS) with automated fluorescence
microscopy and image analysis based technology
was used to develop cellular assays that detect key
mechanisms considered relevant to DILI.
The
following parameters were evaluated: cell
proliferation (nuclear dyes): apoptosis (antibodies to
activated caspase 3); cell cycle (antibodies to
pHistone H3); stress (antibodies to HSP70/72);
reactive oxygen species (ROS) generation (H2DFFDA
staining), and mitochondrial damage (TMRE
staining). Experiments were undertaken in human
primary hepatocytes and in HepG2 cells at 4, 24 and
48 hrs. In addition, in some studies S9 liver fractions
from Arochlor induced rats were added
extracellularly to overcome the inherent metabolic
limitations of HepG2 cells. In HepG2 cells dosed with
cyclophosphamide (CP), an effect on cellular
proliferation and induction of apoptosis was
observed in the presence of S9, but not in the
absence of S9, which is consistent with the
metabolism of CP to toxic metabolites. No effect
was observed in the absence of S9 or NADPH. In
addition, a concentration dependent decrease in
expression of pHistone H3 was observed with CP in
the presence of S9 after 24 hours of exposure but
P118
ENHANCED
DELIVERY
OF
INTRANASALLYADMINISTERED NUCLEOSIDE DRUGS TO THE
CENTRAL NERVOUS SYSTEM Mansi Krishan1, Gary
Gudelsky2, Pankaj Desai2 and Mary Beth Genter1
1
Environmental Health and 2 College of Pharmacy,
University of Cincinnati
Delivery of therapeutics to the brain to treat
neurological diseases and other central nervous
system (CNS) disorders is a challenge due to the
impenetrable nature of the blood brain barrier
(BBB). Intranasal (IN) drug administration is a noninvasive approach for rapid direct delivery from the
nasal cavity to the CNS, thereby minimizing systemic
exposure. The pathways along olfactory and
trigeminal nerves innervating the nasal passages are
involved in the nasal uptake of drugs by transcellular
or transneuronal transport. Other agents are
believed to access the CNS from the nasal cavity by
moving between the epithelial cells, a process called
paracellular transport. On the basis of previous
reports, the current study focuses on the use of the
IN route for direct delivery of the nucleoside drug
gemcitabine (GEM) to treat brain tumors. GEM is
structurally similar to zidovudine (AZT), the latter of
which can be delivered to the brain by the IN route.
In order to enhance drug delivery to the CNS, we
propose to use papaverine (PV), which has been
demonstrated to transiently increase the
permeability of the brain-tumor barrier (BTB) and
BBB after systemic administration. We hypothesize
that by transiently increasing the permeability of
nasal epithelial tight junctions, we will increase the
concentration of GEM in the brain extracellular fluid
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
(BECF) following intranasal drug administration, with
the goal of delivering therapeutic concentrations of
nucleoside drugs to treat HIV dementia and brain
tumors. Experimental methods include in vivo brain
microdialysis for collection of BECF to analyze drug
levels, in vitro recovery of GEM, and HPLC analysis to
measure the concentration of GEM in BECF. A nontoxic dose of PV, which enhanced delivery of GEM to
BECF, was determined. BECF pharmacokinetics of
GEM shows AUC=6.95±1.17 μg.h/ml for PV (1.4%) +
GEM- (50mg/kg) treated animals (n=3) and it is
comparable to the AUC values when GEM and
another BBB permeabilizer (RMP-7) were
administered intravenously. Thus, it appears that
transient permeabilization of nasal epithelial tight
junctions can enhance delivery of nucleoside drugs
to the CNS.
200 series – Test Systems
2011
P200
UNIFORM ULTRASTRUCTURAL CHANGES IN PC12
NEURONAL CELLS EXPOSED TO THREE DIFFERENT
PROTEASOME INHIBITOR CHEMOTYPES
Vilmos
Csizmadia, Lee Silverman, Matthew Gallacher, Kym
Cardoza, Eric R. Fedyk, Carl L. Alden, Bernard Jortner
and Vivek J. Kadambi, Millennium: The Takeda
Oncology Company, Cambridge, MA, USA
Proteasome inhibitors (PIs) have the potential to
cause peripheral neuropathy. This peripheral
neuropathy has been linked to development of
multifocal ubiquitin-positive protein aggregates
(UPAs) in vivo and in vitro. In a mouse model of PIinduced peripheral neuropathy, UPAs appeared in
the dorsal root ganglion cells; nerve injury
subsequently developed. In differentiated PC12
neuronal cells exposed to PIs from 3 chemical
scaffolds (peptide boronate, peptide epoxyketone
and a lactacystin analog), correlative UPA formation
was observed. To further dissect these effects in
neurons, differentiated PC12 neuronal cell cultures
were exposed to these 3 PI chemotypes at the
concentrations resulting in 90%±5% inhibition of 20S
proteasome activity (IC90) and at the concentrations
resulting in 50% cell death (LD50). Cellular effects
were assessed by electron microscope (EM) imaging.
All treatments elicited similar microscopic changes:
in the dying cells prominent juxtanuclear inclusions
with varying size, loss of surface microvilli,
diminished organelles in the peripheral regions and
swollen nuclei and other cytoplasmic organelles. The
inclusions were structurally consistent with
aggresomes.
In
addition,
ultra-structural
observations indicated that necrotic cell death had
occurred. In conclusion, consistent with the earlier
findings on mechanism-based UPA formation in
PC12 neuronal cells, EM images show that PIs induce
qualitative ultra-structural changes regardless of the
chemical scaffold of the PI. Thus, these effects in
vitro are mechanism-based, not chemistry-based.
P119
METHODS FOR EXTERNAL VALIDATION AND
INTERPRETATION OF (Q)SAR MODELS FOR
PREDICTING GENOTOXIC IMPURITIES Joseph F.
Contrera, Ph. D., Computational Toxicology Services
LLC, P.O. Box 1565 Olney, MD. Kevin P. Cross, Ph.D.,
Leadscope, Inc., 1393 Dublin Road, Columbus, OH
The proposed ICH M7 draft guidance on
submission of new drug approvals to regulatory
agencies includes the opportunity to submit in silico
predictions of genotoxicity instead of Ames tests for
low-level impurities. This issue raises questions
concerning the qualification of robust (Q)SAR models
that are appropriate for predicting genotoxic
impurities. This approach investigates how external
validation sets (such as the public Hansen data set)
should be appropriately used for validation of
(Q)SAR models. Fingerprints representing the
toxicophores of the external validation sets are
compared with model training sets to determine the
how the domains of a (Q)SAR model and validation
set overlap. Performance characteristics specific to
individual toxicophores in the overlapping set are
proposed. Interpretation of individual (Q)SAR
predictions using results contributed from
underlying structural features present as model
descriptors is also investigated. The goal is to help
establish a method of qualifying (Q)SAR models for
predicting genotoxic impurities based on model
robustness and interpretability.
P201
ARSENIC EXPOSURE INFLUENCES HEPATOCYTE
MATURATION
Arnab Bhattacharya1, Pushpa
Dhar2, Raj D. Mehra3
1
Senior Resident, Deptt. of Anatomy, Lady Hardinge
Medical College, New Delhi, India. 2Additional
Professor; 3Professor; Dept. of Anatomy, All India
Institute of Medical Sciences, New Delhi, India.
The effects of sodium arsenite exposure on
parameters of hepatocyte maturation during the
cellular and functional reorganization period (PND 9
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32ND Annual MEETING
- 28) of developing rat liver were studied. Wistar rat
pups belonging to the experimental group received
sodium arsenite (1.5 mg/kg body weight) and the
control group received distilled water by
intraperitoneal (i.p.) route from PND 9 until the day
of sacrifice (PND 29). Perfusion fixed liver tissue was
processed for paraffin embedding and H&E staining.
Fresh liver tissue was processed for Sudan Black B
(SBB) staining and for biochemical estimation of
reduced glutathione (Ellman’s method). Microscopic
observations revealed mature hepatic lobular
pattern along with comparable distribution of
uninucleate and binucleate hepatocytes in the
control and experimental groups. Using an Image
Analysis system (NIS-Elements AR 3.1) increase in
mean nuclear area (34.42 ± 3.28 µm²) and nuclear
diameter (6.65 ± 0.31 µm) of hepatocytes was
observed in experimental group. The experimental
group also showed decreased levels of reduced
glutathione (11.23 ± 0.98 µg/g of wet liver tissue).
Lipid droplet distribution pattern (SBB stained)
revealed higher centrilobular staining (mature) in
both the groups and semiquantitative estimation
showed lower cumulative grey values in zone 3
against zone 2 and 1 (suggestive of setting in of the
adult pattern). The developing hepatocytes
(PND 9 - 28) exposed to low dose arsenic showed
increased vulnerability.
pigs were 0% and 8% when compared to telemetry.
For QRS interval, rates of false positives and false
negatives were 0% compared to telemetry. Further,
this model has shown to be sensitive for detection of
AV block and QTc prolongation mediated by hERG,
IKs and IK1 inhibitors and for evaluating the effects of
mixed ion channel blockers on the QTc interval.
Conclusion: The anesthetized guinea pig is a
sensitive model for assessing QTc interval
prolongation and predictive of ECG effects relative to
non-rodent telemetry models. Thus, ECG parameters
can be reliably evaluated using this resource-sparing
small animal model that reduces test article
requirements, reduces the number and cost of
animals, and improves overall data throughput.
Importantly, the design and implementation of this
model is consistent with the "3Rs" for animal
research.
P203
YUCATAN
MINIATURE
SWINE
SURGICAL
GLAUCOMA MODEL DEVELOPMENT AND RESPONSE
TO THERAPY Renna S, Moore C, Liu J, Burks Z, Blair
E, Hanks BC, Horlen K, White D, Brown LD, Bouchard
GF. Sinclair Research Center, LLC
The purpose of this project was to develop a
model of glaucoma via surgical induction of
increased intraocular pressure (IOP) in Yucatan
miniature swine. Three pigs (two female, one male)
had bilateral IOP measurements performed prior to
surgical intervention to establish a baseline IOP for
each animal from which future changes in IOP could
be identified. IOP measurements (mm Hg) were
taken with a Tonopen Vet Tonometer. In order to
reduce venous drainage from the eyes, episcleral
veins were scarified by cauterization in each eye.
IOPs were periodically measured for several weeks
post-cauterization
surgery.
Pharmacologic
intervention was then instituted with a commercially
available synthetic prostamide analog with ocular
hypotensive activity. Drops were applied once daily,
and IOPs continued to be measured. After 7 weeks
of daily treatment, eye drops were discontinued, and
IOP measurements continued to be obtained. All
animals presented with significant increases in IOP
measurements post surgical intervention and
significant decreases in IOP with pharmacological
therapy. Statistical tests included sample mean
comparison by 2-tail T-test P-value (T≤t). Data by
phase as follows-Mean±SD (N readings), P-value:
Baseline:19±4 (65); Post-Surgery: 24±5 (124), ≤0.005
(Baseline vs. Post-Surg); Treatment: 18±4 (75),
≤0.0006 (Post-Surg vs Treatment) Recovery: 20±4
(80), ≤0.006 (Treatment vs Recovery). Therefore,
P202
THE ANESTHETIZED GUINEA PIG: A VALUABLE
CARDIOVASCULAR LEAD OPTIMIZATION SCREEN
Pierre Morissette, Masahiro Nishida, Jeff Travis,
Desiree Steve, Gloria Zingaro, Pam Gerenser, Tara
Grady-Styring, Richard Woltmann, Alysia Chaves,
Ying-Ying Zhou, Greg Friedrichs, Kimberly Hoagland
and Joseph Salata. Merck & Co., Safety Assessment,
West Point, PA.
A resource-sparing in vivo cardiovascular screen is
valuable for the selection of lead drug candidates
early in development prior to the start of longer,
more resource intensive safety pharmacology and
toxicology studies. Our goal was to develop a
sensitive and predictive anesthetized small animal
model to assess effects on ECG that are predictive of
the non-rodent safety pharmacology telemetry
models. We compared the ECG effects of 26
compounds in this anesthetized guinea pig model
with those in non-rodent telemetry models.
Results: ECG effects in guinea pigs were 92%, 100%
and 92% concordant with effects in non-rodent
telemetry for PR, QRS and QTc intervals changes,
respectively. The rates of false positives and false
negatives for QTc and PR interval changes in guinea
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32ND Annual MEETING
the Yucatan miniature swine should be considered a
viable model for surgically induced glaucoma. The
miniature swine eye is also responsive to
pharmacological therapy to reduce IOP and as such
could be a potential model for future
pharmacological research.
P205
THE SLOW ONSET ATRIOVENTRICULAR BLOCK IN A
CONSCIOUS TELEMETERED GUINEA PIG MODEL
Ying-Ying Zhou, Yu-Jing Gao, Richard Tedesco,
Kathryn Pula and Gregory Friedrichs. Merck & Co.,
Safety Assessment, Summit, PA.
Introduction: The most common evaluation of ECG
from both toxicology and safety pharmacology
standard studies is focused on acute and regular
events such as ECG interval changes or arrhythmias.
However, some of these changes are irregular or
develop as a slow onset phenomenon. This case
study highlighted the value of chronic monitoring of
ECG when using a telemetered guinea pig model in
detecting irregular and slow onset atrioventricular
block (AV block).
Methods: Guinea pigs instrumented with
radiotelemetry
transmitters
for
continuous
collection of ECG signals were utilized to investigate
potential chronic cardiac conduction issues with
Merck compound X. A single oral dose study with
vehicle, 10, 30 and 100 mg/kg compound X using a
dose escalating design was conducted initially for
dose range finding. In the repeat dose study which
followed, five guinea pigs were dosed orally with 100
mg/kg compound X and three with vehicle as a
control for 5 days.
Results: The baseline incidence of AV block was low
in naive guinea pigs. Sporadic and slow onset second
degree AV block was noted in 2 out of 3 guinea pigs
following 100 mpk single dose of compound X. The
AV block was preceded by progressive PR
prolongation and followed by PR shortening as a
typical Mobitz type 1 or Wenckebach AV block. The
occurrence of AV block appeared to be dosedependent. The incidence of AV block also increased
with multiple daily doses of compound X with more
than 300 instances of AV block on average at day 4.
Heart rate was significantly decreased after multiple
dosing too. There were no test article related
changes in other measured ECG intervals (PR, QRS
and QT/QTc).
Discussion and Conclusion: The data suggest that
conscious telemetered guinea pig is a sensitive
model to detect irregular and slow onset AV block.
The results are consistent with the findings from dog
and human, although different from preliminary
data from rat and monkey. The potential
mechanisms behind these findings will be discussed.
P204
HOMOZYGOUS AND HETEROZYGOUS P53 KNOCK
OUT RATS DEVELOP METASTASIZING SARCOMAS
WITH HIGH FREQUENCY Ruben Van Boxtel1, Raoul
V. Kuiper1, Pim W. Toonen1, Sebastian van Heesch1,
Roel Hermsen1, Alain deBruin1 , Pamela Riley2, Jack
Crawford 3and Edwin Cuppen1. 1Hubrecht Institute
for Developmental Biology and Stem Cell Research,
Utrecht, The Netherlands.
2
Charles River Laboratories, Wilmington, MA 01887
3
Transposagen, Lexington, KY 40507
The TP53 gene is one of the most extensively
studied tumor suppressor genes and has been found
to be mutated in almost all cases of human cancer.
In designing animal models to mimic the
involvement of TP53 several lines of transgenic mice
have been developed and have shown, when
homozygotes are used, a relatively uniform tumor
spectrum with thymic lymphomas as the dominant
tumor type, and a fast onset of disease. However,
the tumor spectrum when heterozygotes are used is
more diverse and is similar to humans with a slower
onset of tumorgenesis, indicating that a loss of
heterozygosity has to precede tumor development.
Here
we
present
the
first
in-depth
characterization of a TP53 deficiency in the rat,
generated using a target-selected mutagenesis
approach. Homozygous rats, completely lacking
TP53 protein, display a decrease in survival due to
tumorgenesis, developing sarcomas with a high
incidence of pulmonary metastases, at 4 months of
age. In contrast, heterozygous rats exhibit a slower
onset to tumorigenesis with sarcomas developing by
8 months of age. Molecular analysis of these tumors
shows a loss of heterozygosity of the wild type P53
allele. These unique features complement existing
rodent p53 knock out models and provide a versatile
tool for investigating tumorigenesis
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P206
OPTIMAL DURATION OF JACKET HABITUATION
BASED ON CARDIOVASCULAR ENDPOINTS IN
BEAGLE DOGS AND CYNOMOLGUS MONKEYS
Julie Sentz, BS, RLATg, SRA, Danielle Higgins, BS,
RLATg, Jen Sheehan, BS, RLATg, SRS, Mutsumi
Miyamoto, DVM, MS, PhD
The invasive telemetry system and snapshot
recording of ECG are commonly used to monitor
cardiovascular
(CV)
endpoints
in
safety
pharmacology and toxicity studies. Due to the recent
development of non-invasive jacket telemetry
systems, CV endpoints can be monitored for longer
periods on toxicity studies in unrestrained dogs and
monkeys. It is essential to habituate animals to the
jacket prior to the data collection period to obtain
good quality data. The purpose of this study was to
determine the optimal habituation period based on
heart rate response. Heart rate (HR) was collected
from 4 jacketed non-human primates (NHPs)
following 3 consecutive occasions of jacket
habituation. Heart rate was also collected from
jacketed dogs following 3 and 7 consecutive
occasions of jacket habituation. Heart rate data
collected following 3 and 7 day jacket habituation
was compared with the Testing Facility’s historical
control data collected from non-jacketed, invasive
telemetry models in both species. Heart rate
collected from jacketed monkeys (following 3 day
habituation) and dogs (following 3 and 7 day
habituation) are comparable to data from nonjacketed animals. Therefore, we concluded that a
three day habituation is optimal to prevent
undesirable effects in the CV data that may result
from insufficient jacket habituation.
Index Terms: 1. Jacket Habituation 2. Telemetry 3.
Safety Pharmacology
technologies can be applied to help understand the
underlying pathology induced after toxic insult.
Evotec has developed a medium throughput
semi-automated histology platform capable of
simultaneously capturing full-body histological
sections from up to 50 zebrafish larvae. This
approach offers the opportunity to integrate diverse
histological endpoints into the established zebrafish
screening assays.
In this study, 12 compounds with known
hepatotoxic liabilities were assessed using a
combined phenotypic and histological screening
approach. Zebrafish larvae were treated for 48hr
with up to four concentrations of compound
alongside a vehicle control, scored for liver
abnormalities and sectioned using the histology
array. Liver tissue in sequential sections was
assessed for morphological alterations (H&E stain),
glycogen levels (periodic acid-Schiff stain) and
fibrosis (trichrome stain). The outcome of how these
histological data support the morphological analysis
will be reported.
P208
DIFFERENTIATION BETWEEN DEVELOPMENTAL AND
ACUTE TOXICITY OF DRUG LIKE COMPOUNDS
USING ZEBRAFISH
Hill, A, Michael Richardson,
Jones, M, Diekmann H. Evotec (UK) Ltd, Abingdon,
United Kingdom
Zebrafish have gained increasing popularity for
toxicity testing over the past decade due to
numerous advantages over other vertebrates,
including the use of an in vitro-like assay format in
multi-well plates, requiring only single milligrams of
test compound for a full dose response and the
transparency of the zebrafish larva, which decreases
the need for invasive procedures and dissection.
Evotec previously evaluated its zebrafish
developmental toxicity assay by testing 90 blinded
compounds. In comparison to results from
mammalian embryo-foetal developmental toxicity
studies, the zebrafish assay was ~90% predictive for
identifying toxic compounds. One key challenge
highlighted in the study was the need to distinguish
distinct embryotoxic effects from acute toxicity
(effects that would commonly be detected as
maternal toxicity in mammalian assays).
In the current study, 20 compounds with known
teratogenic liabilities were assessed using a
combined embryonic and larval screening approach.
Zebrafish were treated for 96hr with five
concentrations of compound alongside a vehicle
control and scored for morphological abnormalities
and lethality throughout the assay. Since compound
P207
HIGH CONTENT ZEBRAFISH HISTOLOGY:
NEW
DIRECTIONS IN EARLY DRUG SCREENING
H Diekmann, A Dodd, A Cracknell, O Murphy, M
Jones and A Hill. Evotec (UK) Ltd, Abingdon, United
Kingdom
In recent years, zebrafish larvae have emerged as
an exciting and predictive in vivo platform for
assessing toxic liabilities of compounds early in the
drug development process. These assays often rely
on relatively simple morphological or behavioural
readouts to allow a medium to high throughput for
screening. Although these readouts are predictive
for identifying toxic compounds, in order to realise
the full value of this platform, high content
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
uptake by zebrafish larvae could vary during
development, the actual body burden (ng/larva) was
determined at the respective NOECs and LOECs for
both embryos and larvae via LC-MS. A comparison of
toxicity exhibited in embryonic versus larval
zebrafish together with how this outcome supports a
classification for teratogenic and/or embryotoxic
compounds will be reported.
encouraged to plan EFD/ePPND studies as far in
advance as possible
P210
COMPARISON
OF
BASIC
COAGULATION
PARAMETERS FOR CYNOMOLGUS MACAQUES
(Macaca fascicularis) FROM DIFFERENT SOURCES.
Donald Waller1, Elizabeth McGeehan2, Jean Dubach3,
Debra A. Hoppensteadt2, Jawed Fareed2, Il , 1Prelabs
LLC, Oak Park, IL, 2Loyola University, Maywood, Il,
3
PrimGen LLC, Oak Park, IL
Non-human primates are used extensively for
anticoagulant therapy development. Availability,
cost and size has led to an increased use of M.
fascicularis (cynomolgus) for testing. Differences for
coagulation responses between M. mulatta and M.
fascicularis were previously demonstrated and, in
addition, genetic diversity among macaques from
different sources has also been observed. The
present study examines potential disparities of
coagulation responses for animals attributed to
sources in Vietnam, Philippines, Indonesia, China and
Mauritius. The coagulation cascade is evaluated by
determination of clotting tests such as prothrombin
time (PT), activated partial thromboplastin time
(aPTT), common pathway (Heptest®), and thrombin
time (TT). Blood was drawn and immediately
transferred to sodium citrate tubes (3.2% at 9 parts
blood to 1 part sodium citrate), centrifuged to obtain
plasma and stored at -80oC. Clotting tests performed
included PT, aPTT, Heptest®, and TT assays using the
ACL 300+ and BBL Fibro System manual fibrometers.
PT values, regardless of source, were within a range
of + 2 seconds. Similar results were also observed
for the aPTT data. However, Heptest® values
appeared to vary with animal source. The lowest
values (mean 16.4) were observed for the
Vietnamese and the highest values (mean 24.5) for
Mauritius sourced animals. Thrombin Time had the
largest variance in values, but no differences
between sources were observed. The data show
differences for some coagulation parameters
depending upon the source of the animals. It is
essential to identify the source of animals and
determine baseline values for studies in which
coagulation parameters play a major role. A clear
understanding of these differences is essential when
interpreting past data and assessing new
anticoagulants
for
efficacy,
safety
and
pharmacokinetics.
P209
NONHUMAN PRIMATE MODELS IN PRECLINICAL
REPRODUCTIVE TOXICOLOGY: OPPORTUNITIES AND
IMPLEMENTATION OF THE ICH S6(R1) GUIDELINE
N. Makori1, N. Lalayeva1, R. Watson1, S. Oneda1, P.
Franklin1, T. Beck1, R. Nagata2
1
SNBL USA, Ltd., Everett, WA, USA; 2Shin Nippon
Biomedical Laboratories, Ltd., Kagoshima, Japan.
The ICH S6(R1) guideline was issued in June 2011.
Part of the guideline specifically addresses study
design elements and study initiation timing in
nonhuman primates (NHPs). Embryo-fetal (EFD) and
enhanced pre/postnatal (ePPND) studies may be
conducted prior to or concurrently with Phase III
clinical trials. Initiating studies concurrent with Phase
III will require extremely stringent timelines. In
collaboration with pharmaceutical companies,
contract research laboratories that offer these
resource- and time-consuming EFD/ePPND studies in
NHPs may need to shorten study timelines. One of
the approaches to consider is expedited enrollment
of pregnant animals to study. For example, instead
of 16 weeks to fill a 60-animal study, the duration
would be 10 weeks. This may require adjustments
both to resource management and the approach to
breeding practices. One key factor to take into
account is the historical rates of pregnancy loss in
NHPs unique to each laboratory setting. The
question then is, will the pregnancy loss rates
compromise the timing by requiring replacement
animals on study? As an example, of 398 pregnant
monkeys in our facility between 2007 and 2011,
there was 17.8% embryo/fetal loss on or before
gestation day 130 (GD130), 2.5% infant loss due to
premature birth (viable or dead infant) between
GD131 and GD145, and 15.3% loss due to non-viable
births (delivery of dead infant on or after GD146).
Even though these loss rates are within normal
historical values and published data, three of the 24
studies
(13%)
required
additional
animal
replacements resulting in an extension of the study
timelines. To cater for potential animal replacements
and other unforeseen events that may result in
extensions of study timelines despite potential
decrease in enrollment duration, it is always
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P211
COMPARISON OF CYNOMOLGUS (MACACA
FASCICULARIS) AND HUMAN MICROSOMAL
METABOLISM OF A CYP 450 PHENOTYPING
COCKTAIL
Joseph McGraw1, Steven Scholzen1,
2 1
Donald Waller , Concordia University, Mequon, WI,
2
Prelabs LLC, Oak Park, IL
Cynomolgus monkeys are often used as a
surrogate model for human CYP 450 mediated
metabolism. Cynomolgous monkeys share similar
CYPs as humans with a high percentage of amino
acid sequence homology. Major human CYPs and
homolgous Cynomolgous monkey CYPs (Cyno CYP, %
amino acid sequence homology) are as follows: 1A2
(1A2, 93), 2C9 (2C43, 93), 2D6 (2D17, 93), 2E1 (2E1,
94), and 3A4 (3A8, 93). A UHPLC/MS/MS CYP 450
phenotyping assay was used to compare the major
human CYP 450s to the cynomolgus monkey using
in-vitro microsomal incubations. Microsomes were
prepared from cynomolgous monkeys and compared
to pooled human microsomes. UHPLC separation
was carried out on a Waters Acquity HSS T3 1.8mcm
(2.1x100mm) column with an Acquity HSS T3
1.8mcM Vanguard Pre-Column. Compounds were
eluted with a gradient of Acetonitrile/ THF/ Formic
Acid (20/ 4/ 0.1) in methanol. Mass spectrometry
detection was carried out with a AB Sciex 4000 Qtrap
triple quadrupole mass spectrometer equipped with
a Turbo V IonSpray as an LC/MS interface. Positive
ion mode ESI mass spectra were acquired from
microsomal extracts for the following probes
(corresponding CYP 450 in parenthesis): caffeine
(1A2), dextromethorphan (2D6 and 3A4), and
testosterone (3A4) along with their metabolites
paraxanthine, dextrorphan, hydroxymorphinan, and
6-beta hydroxytestosterone. Negative ion mode was
used to identify probes (CYP 450): chlorzoxazone
(2E1) and diclofenac (2C9) along with their
metabolites
6-hydroxychlorzoxazone
and
4hydroxydiclofenac.
Incubations
show
large
differences in dextromethorphan metabolism, which
was a probe for 2D6 (dextrorphan) mediated
metabolism
and
3A4
(hydroxymorphinan)
metabolism.
eywords: cynomolgous, CYP 450, phenotype,
metabolism, probe
There is a need for better models to assess the
safety of biologics and for testing human specific
therapies. The NSG mouse presents a unique
opportunity to establish the human immune system
in vivo. The objective of this project was to establish
the efficacy of utilizing the humanized mouse in drug
development and safety.
We standardized 3 protocols for humanizing the
NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice
engrafting human CD34+ stem cells (HSC) at P0 to P2
by intracardiac injection or in juveniles via tail vein
injection. In juveniles donor matched liver and/or
thymus can be co-transplanted.
Humanized NSG mice express B and T cells, T
helper cells, cytotoxic T cells, dendritic cells and
monocytes and other. The cells types are expressed
in ratios similar to what is seen in humans. The mice
have shown immune system functionality in delayed
type hypersensitivity models and in the dextran
sodium sulfate model of inflammatory bowel
disease. Preliminary data also indicates that the
model is suitable for safety studies to assess the
immunogenicity of biologics.
The humanized mouse is an invaluable tool for
modeling infectious diseases restricted to the human
host providing an option to the use of non-human
primates; however the applications for this model
extend much further. Complications of the use of
biologics include the induction of acute
inflammatory responses and the humanized mouse
makes an ideal tool for early assessment of the
immunogenicity of biologics. Additionally, the
humanized mouse is an ideal tool for assessing
human specific therapies targeting the immune
system.
P213
INTEGRATION OF PIG-A, MICRONUCLEUS AND
COMET ASSAY ENDPOINTS IN 28-DAY RODENT
TOXICITY
STUDIES
WITH
7,12DIMETHYLBENZ(a)ANTHRACENE
(DMBA)
AND
DIETHYLNITROSAMINE (DEN) LF Stankowski, Jr1, B
Krsmanovic1, S Bruce1, T Kelley1, M Paranjpel1, K
Szabol1, S Springer1, J Sly1, M Klug-LaForce1, M
Arevalo1, S Atta-Safoh1, F Debelie1, P Sareen1, S
Dertinger2 and J Shi1 1BioReliance Corporation,
Rockville, MD, United States, 2Litron Laboratories,
Rochester, NY, United States
As part of a multi-lab validation, we examined
induction of Pig-a mutant red blood cells (RBCs) and
reticulocytes (RETs) by flow cytometry (FCM) during
28-day subchronic studies in male Sprague-Dawley
rats treated with 2.5, 5 and 10 mg/kg/day DMBA, or
5, 10, 20 and 35 mg/kg/day DEN. The same animals
P212
HUMANIZING
THE
NOD.CG-PRKDCSCID
IL2RGTM1WJL/ SZJ FOR USE IN DRUG SAFETY AND
DEVELOPMENT Amen Phagura1, Ryan Rodriguez1,
Jared Bagley1, Elizabeth Ontano1, Leon Hall 1 1The
Jackson Laboratory, 4910 Raley Blvd, Sacramento CA
95838
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
were analyzed for micronucleated RETs (mnRETs) in
peripheral blood by FCM, and DNA damage in liver
via Comet assay. Also analyzed were Comet
response in peripheral blood (DEN-treated animals),
or micronucleated polychromatic erythrocytes
(mnPCEs) in bone marrow (DMBA-treated animals,
by manual scoring). DMBA induced dose-related
increases in Pig-a mutant RBCs and RETs (Days 15
and 29), mnRETs (Days 4 and 29), and mnPCEs (Day
29), but no increase in Comet response was
observed in liver at doses up to 10 mg/kg/day, which
appeared to be below the MTD (upon re-testing up
to 200 mg/kg/day for 3 days in a follow-up acute
study, DMBA induced a positive Comet response in
liver, but was negative in peripheral blood). In
contrast, DEN was negative for induction of Pig-a
mutant RBCs and RETs (Days 15 and 29) and mnRETs
(Days 4 and 29), but induced dose-dependent
increases in Comet response in liver and blood (Day
29), at doses up to 10 mg/kg/day (higher dose
groups were terminated early due to excessive
toxicity/mortality). These results emphasize the
extreme care that must be taken in dose and
endpoint selection when incorporating genotoxicity
endpoints into routine toxicity studies.
(the latter as in a typical Comet/micronucleus combo
assay). Dose-related increases were observed for
Pig-a mutant RBCs and RETs (15 and 29 days after
last dose), mnRETs (3 days after last dose), and
Comet responses in PBLs, liver and stomach (3 hours
after last dose). Except for Pig-a mutant RETs and
RBCs, all responses decreased at the later
timepoints.
Dose-dependent
increases
in
micronucleated bone marrow polychromatic
erythrocytes also were observed 3 hours after the
last of 3 doses, but no increase in CAb was observed
in PBLs, possibly due to technical issues. These
results emphasize the extreme care that must be
taken in dose and endpoint selection when
incorporating genotoxicity endpoints into routine
toxicity studies as recommended in ICH S2(R1).
P215
AN
EXPLORATORY
EFFICACY
STUDY
OF
PULMONARY ARTERIAL PRESSURE IN SPRAGUEDAWLEY RATS, D. Poulin1, K. McInally1, J. Gizzi2,
H. Bogie2. 1ITR Canada, Montreal, Quebec 2 Data
Sciences International, St-Paul, MN
The objective of the study was to evaluate the
pulmonary artery pressure (PAP) of Sprague-Dawley
rats, equipped with a telemetry implant, when
administered U-44069, a PGH2 analog, similar to
endogenously formed thromboxane A2 which can be
titrated to induce the desired degree of pulmonary
vasoconstriction, 3 times a day.
Prior to the study, rats had a subcutaneous
telemetry device implanted and the catheter was
placed in the right ventricle and advanced into the
pulmonary artery.
Rats received intravenous infusions of U-44069
at a formulation concentration of 0.5 mg/mL,
administered for 15 minutes at a dose rate of 10
mL/kg/hr, 3 times per day, separated by
approximately 1 hour. Additional control rats were
kept in the restrainer and followed the same
regimen (ie. 3 times per day).
The PAP increases were similar after each
administration, although slightly less significant
increases were observed after the second and third
administrations. However, there were still
significant increases in PAP of at least 51%, and
therefore, it is considered that multiple daily
administrations are appropriate for this model.
In addition, there were no significant changes in
PAP in control animals, therefore the restraint
procedure is not considered to have an impact on the
evaluation and interpretation of the data with this
model.
P214
INTEGRATION
OF
PIG-A,
MICRONUCLEUS,
CHROMOSOME ABERRATION AND COMET ASSAY
ENDPOINTS IN RODENT TOXICITY STUDIES WITH 4NITROQUINOLINE-1-OXIDE (4NQO): EFFECT OF
DOSE FRACTIONATION ON GENOTOXIC RESPONSES
LF Stankowski, Jr1, DJ Roberts2, H Chen3, T Lawlor3, M
McKeon3,
H
Murli3,
3
3
1
A Thakur and Y Xu
BioReliance Corporation,
Rockville, MD, United States, 2Bristol-Myers Squibb,
New Brunswick, NJ, United States, 3Covance
Laboratories, Inc., Vienna, VA, United States
As part of a multi-lab validation, we examined
induction of Pig-a mutant red blood cells (RBCs) and
reticulocytes (RETs) by flow cytometry (FCM) during
a 28-day subchronic study in male Sprague-Dawley
rats using 4NQO. Animals also were analyzed for:
micronucleated RETs (mnRETs) by FCM; DNA
damage in blood, liver, and stomach by the Comet
assay; and chromosome aberrations (CAbs) in
peripheral blood lymphocytes (PBLs). Dose-and timerelated increases were observed in Pig-a mutant
RBCs and RETs (Days 15 and 29), as well as mnRETs
(Day 29, but not Day 4). No increases were observed
in PBL CAbs (Days 4 and 29), or DNA damage in liver
(Days 15 and 29), stomach (Day 29), or PBLs (Days 1,
15 and 29). A follow-up study was performed at the
same cumulative doses given in 1 or 3 daily doses
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P216
TESTICULAR AND EPIDIDYMAL HISTOLOGIC
CHANGES AROUND THE PERIOD OF SEXUAL
MATURATION IN YUCATAN BOARS
T. Evans,
University of Missouri, Columbia, MO, J. Trickey, L.
Brown, G. Bouchard, Sinclair Bio-Resources LLC,
Auxvasse, MO
Preclinical guidelines often specify the use of
prepubertal, pubertal, or sexually mature animals.
However, “puberty” and “sexual maturity” can be
defined in a number of different ways which reflect
androgen production, including the onset of
mounting behavior, penile erection and/or
ejaculation ± sperm capabilities, or, histologically, by
a “threshold” portion of seminiferous tubules
engaged in spermatogenesis ± epididymal sperm.
Furthermore, “sexual maturity” can also be
interpreted slightly differently, depending on the
type of toxicology study programs (e.g., DART versus
repeat dosing studies). Since Yucatan boars have
been reported to reach “puberty” as early as 12
weeks or as late as 16 to 20 weeks of age, it is
critical, regardless of how the stages of sexual
development are defined, to know what is
happening histologically in the testes at these
various ages. Modified Davidson’s-fixed and PASstained testicular and epididymal sections were
evaluated from 12-, 14-, 16-, 18-, 20-, 22-, and 24week-old Yucatan boars (n=minimum of 4/age
group). Approximately 200 seminiferous tubules
were evaluated per testis for the presence of round
spermatids only (immature tubules), as well as for
species-specific cellular associations (stages)
involving round and/or elongate spermatids
(“mature” tubules). The proportion of the total
number of seminiferous tubules represented by
“mature tubules” was calculated. The presence of
sperm in the caudae epididymides was also noted.
Round spermatids began to appear at 12 weeks of
age, and a majority of 14-week-old boars had
seminiferous tubules containing both round and
elongate spermatids. While sparse numbers of
sperm appeared in the epididymides of one boar at
14 weeks of age, at least half of the 16- and 18week-old boars exhibited some spermiation with
sperm in the excurrent duct system. By 20 weeks of
age almost all seminiferous tubules were “mature”,
with sperm present in the epididymides. These novel
data can be taken into consideration, along with
other indices of sexual development, when designing
toxicology experiments of varying durations which
require Yucatan boars at a given stage of sexual
maturity.
300 series – General Toxicology
P300
DETECTION OF IBUPROFEN IN POSTMORTEM
RAT TISSUES
Prof. Dr. M.H. El Karadawey*, M.fa
Elden**, Mohamed H. Kreet***, Head of Medico
Legal of Great Cairo Area, Ministry of Justice, Cairo,
Egvypt. ** Department of Toxic and Narcotic
DrugForensic Medcine, Ministry of Justice, Egypt.
*** Department of Toxic and Narcotic Drug Forensic
Medicine, Ministry of Justice, Egypt
Iboprofen is an Analgesics which mainly used for
the relief of mild or moderate pain and some of
which have antipyretic actions. Many analgesics
have marked anti-inflammatory actions and are used
in the treatment of arthritis, rheumatism and other
inflammatory conditions. This study was done to
detect quantity of Ibuprofen in different organs after
death in albino rat organs.
The quantitative
estimation of ibuprofen residue in postmortem
albino rat organs was done by high performance
liquid chromotogrpahy (HPLC) using methanol:water
(80:20) as solvent and eluent at λ= 274 nm with flow
rate 2ml/min . and C18 column. The concentration
of ibuprofen residue in different tissues and blood
was obtained where brain and kidney were found to
be the organs which have the highest concentration.
Ammonium sulphate method was used for
extraction and purification for blood and tissue
specimens. The present study would be of great
importance for investigation of any overdoes
toxicological mystery death of ibuprofen and we can
conclude that the best organ of postmortem
sampling as it has the highest concentration
ibuprofen and it can help us in extracting ibuprofen
to be identified and detected.
P301
HOMIDIUM
CHLORIDE
AND
DIMINAZENE
ACETURATE MODULATED BIOCHEMICAL AND
MORPHOLOGICAL CHANGES IN TRYPANOSOMA
BRUCEI BRUCEI-INFECTED RATS
*1Adeyemi, O.S.
1
1
and Sulaiman, F.A. * Redeemer’s University,
College of Natural Sciences, Department of Chemical
Sciences, PMB 3005, Mowe-121001, Nigeria,
1
University of Ilorin, Department of Biochemistry,
PMB 1515, Ilorin, Nigeria, Correspondence to
yomibowa@yahoo.com
Study presented effects of two trypanocides
(Novidium® - homidium chloride and Berenil® diminazene aceturate) on the pathology of tissues
and selected parameters in an experimental
infection by Trypanosoma brucei brucei. Data
revealed significant (p<0.05) increases in the
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
activities of alkaline phosphatase (ALP), alanine
transaminase (ALT) and aspartate transaminase
(AST) of infected rats compared to the uninfected
animals. ALP and AST activities in the infected
animals treated with novidium® showed a
significantly (p<0.05) lower values relative to the
infected positive control animals. In contrast ALT
activity was higher (p<0.05) in novidium® treated
rats. There was no significant (p>0.05) difference
between the activity of ALP in infected group and
the animals treated with berenil®. Activities of ALT
and AST in the berenil® treated animals were
however significantly (p<0.05) increased relative to
the other groups. Histopathological examination of
tissues from T. b. brucei infected animals revealed
loss of tissue architecture with pronounced presence
of inflamed cells and haemorrhage. Treatment of
infected animals with the trypanocides however did
little to restore the integrity of damaged tissues
when compared to the uninfected control group.
Results underscores further the need for new and
improved trypanocides moreso that chemotherapy
is one of the major ways for controlling
trypanosomal infections.
pharmacologically-mediated depletion of blood and
bone marrow eosinophils was observed. An instance
of transient petechiae and ecchymosis, decreased
platelet count, and indicators of circulating
erythrocyte mass occurred in one female in the
25 mg/kg IV dose group after the fourth dose
(Day 43). After a dosing holiday on Day 57, this
animal remained on study with continued
benralizumab dosing (Platelet values and red blood
cell mass in this animal fluctuated after dosing was
resumed but were near baseline levels by the end of
the dosing period and lacked any correlating
macroscopic or microscopic findings at scheduled
necropsy). There were no benralizumab -related
effects observed including no effects on male and
female fertility parameters. Under the conditions of
this study, the benralizumab NOAEL was
25 mg/kg/dose (IV) and 30 mg/kg/dose (SC), the
highest doses evaluated for each route of
administration.
P303
A NOVEL APPROACH FOR CONTINUOUS OR
INTERMITTENT SUBCUTANEOUS INFUSION USING
SINGLE OR MULTIPLE SITES IN MINI-PIGS,
Prefontaine A., Trudel Y., Caron S., Copeman C.,
Charles River Laboratories
The mini-pig is considered a suitable model for
local tolerance and safety assessments of
formulations administered subcutaneously because
skin and subcutaneous space closely resembles that
of humans.
Consequently, the feasibility of
continuous subcutaneous infusion (24 hrs) utilizing a
daily rotation of sites, in the Göttingen Mini-pig was
evaluated over 10 days. Using two mini-pigs (12.8
and 19.0 kg, respectively), a subcutaneous tissue
infusion set was inserted through the skin and
secured in place using adhesive dressing. The minipig was fitted with a jacket connected to a tether
system and the cannula to a swivel and external
infusion pump. Saline was continuously infused (2.5
mL/h) subcutaneously, through a 0.22 µM filter, at
sites between the scapular and lumbar thoracic
regions for 10 days alternating through different site
each day. Parameters evaluated were daily detailed
examinations, weekly body weights, daily food
evaluation, clinical pathology evaluations (Days 1, 3,
5, 7, and 10), macroscopic and microscopic
examinations. Continuous subcutaneous infusion
was successfully conducted for 10 days.
As
expected, no adverse effects in parameters of
systemic toxicity were seen and no unexpected
events were encountered during blood collections.
Local responses of slight, well-defined areas of
P302
AFUCOSYLATED ANTI-IL-5 RECEPTOR ALPHA
ANTIBODY (BENRALIZUMAB): NINE MONTH
CHRONIC TOXICOLOGY STUDY IN SEXUALLY
MATURE CYNOMOLGUS MONKEYS.
Manetz, TS,
Leininger, JR, Wang, B, Ryan, PR, Kolbeck, R, and
Dixit, R.
MedImmune, LLC, Gaithersburg, MD USA.
Benralizumab (MEDI-563) is a humanized,
monoclonal antibody that specifically binds to the
human interleukin-5 receptor alpha subunit
expressed predominantly on eosinophils, a cell
believed to play a functional role in bronchial
asthma. Similar to the mechanism of other anti-IL-5
antibodies, benralizumab blocks the binding of IL-5
to its receptor, but benralizumab was also
engineered to be afucosylated, which is anticipated
to result in enhanced ADCC-mediated destruction of
eosinophils and basophils, offers a novel approach to
asthma treatment. To support benralizumab clinical
development for the treatment of asthma, a chronic
intravenous infusion (10 or 25 mg/kg) or
subcutaneous (30 mg/kg) dose study was performed
in cynomolgus monkeys (6/sex/group) with
benralizumab administration every other week for
39 weeks (20 total doses).
Necropsies were
performed 3 days and 12 weeks after the final
benralizumab dose administration. Following
repeated benralizumab administration, the expected
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32ND Annual MEETING
erythema and dark areas and/or swelling at the
infusion sites were noted macroscopically.
Microscopically, some procedure-related findings of
minimal or slight inflammation, hemorrhage and/or
necrosis were noted, however the adjacent skeletal
muscle was unaffected. The low incidence and
severity of the local responses at the infusion sites
were considered unlikely to hinder study
interpretation. In conclusion, 24 hour subcutaneous
infusion in the Gottingen Mini-pig was well tolerated
systemically and presented minimal experimental
background changes. Indications of recovery at the
infusion sites suggest that repeat administration at a
given site may be acceptable with an appropriate
recovery period between administrations.
dose volume of 2 mkd minimized the incidence of
loose/watery feces and emesis.
P305
AN 85-DAY REPEAT DOSE TRANSCUTANEOUS
TOXICITY STUDY OF AN ENTEROTOXIGENIC E. COLI
VACCINE IN NEW ZEALAND WHITE RABBITS.
Godin, C.S.1; Wenzel, H.2; O’Dowd, A.3; Maciel, M.3;
Poole, S.3; Bourgeois, A.L.4; Savarino, S.3 1AVANZA
Laboratories, LLC, Gaithersburg, MD; 2ABL, Inc.,
Rockville, MD; 3Naval Medical Research Center,
Silver Spring, MD; 4PATH, Washington, DC
A vaccine against enterotoxigenic E. coli (ETEC) is
being developed for travelers and young children at
high risk of ETEC diarrhea. The purpose of this study
was to determine the potential toxicity and
immunogenic potential of the vaccine when
administered alone or with an enterotoxin adjuvant
to New Zealand White (NZW) rabbits by the
transcutaneous route. This study was also designed
to determine the persistence, late onset, or
reversibility of any toxic effects over a 20-day notreatment
recovery
period.
NZW
rabbits
(14/sex/group) were assigned to the study and were
treated via wet skin patch with either PBS; vaccine
(250 µg/dose); adjuvant (50 µg/dose); or both
vaccine (250 µg) and adjuvant (50 µg) on Study Days
(SD) 1, 22, 43, and 64. Two animals/sex/group were
sacrificed on SD 3 (interim), six animals/sex/group
were sacrificed on SD 66 (terminal), and the
remaining animals were sacrificed following the
recovery period on SD 85 (recovery). Parameters
evaluated included mortality, physical examinations,
cageside observations, dermal Draize observations,
measurement of dosing sites, body weight and
changes, body temperatures, humoral responses to
the vaccine and adjuvant, clinical pathology (serum
chemistry, hematology, coagulation, and C-reactive
protein), gross pathology, organ weight data, and
microscopic pathology. When administered alone or
together, treatment with the adjuvant or vaccine did
not produce systemic toxicity. Treatment with the
adjuvant alone or in combination with the vaccine
was associated with dose site reactions, including
erythema, edema, and inflammation; however,
these findings were transient and non-adverse.
Treatment with the vaccine alone was not associated
with dose site reactogenicity. Both the vaccine and
adjuvant were highly immunogenic.
P304
TWENTY-EIGHT DAY TOXICITY STUDY WITH THE
NON-TRADITIONAL VEHICLES PEG 400 WITH EITHER
SOLUTOL™ HS15 OR CREMOPHOR ™ RH 40 IN
BEAGLE DOGS
Daniel Kemp1, Brenda Faiola1,2,
James Hailey1, Holly Jordan1, Christine Merrill1,
Randy Brown1, David Bailey1 1 Safety Assessment,
GlaxoSmithKline, Research Triangle Park, NC, USA 2
Currently at RTI International, Research Triangle
Park, NC, USA
This study determined the tolerability and toxicity
of various formulations of Solutol/PEG 400 on
female dogs and Cremophor/PEG in male dogs, in
two 28-day, oral, repeat-dose studies. Five groups of
3 female dogs were given either water vehicle, 10%
Solutol/90% PEG (2 mL/kg/day (mkd)),
30%
Solutol/70% PEG (2 mkd), 10% Solutol/90% PEG (5
mL/kg/day), or 30% Solutol/70% PEG (5 mkd). All
dogs tolerated the administration of 10%
Solutol/90% PEG or 30% Solutol/70% PEG ( 2 mkd).
Three groups of male dogs were given either water
vehicle or 10% Cremophor /90% PEG at a dose
volume of 2 or 5 mkd. Loose/watery feces and
minimal mucus-cell hyperplasia of the ileum were
present in all Solutol groups. Total bilirubin was
minimally ↑ at all doses of Solutol. ↑ red blood cell
mass and ↓ urine volume in animals given 30%
Solutol/70% PEG (5 mkd) were likely due to
subclinical dehydration and hemoconcetration
associated with the loose/watery feces. Emesis was
present in all animals given Cremophor with a dose
volume-dependent ↑ incidence of emesis and
minimal
subepithelial
gastric
hemorrhage.
Minimally ↑ serum urea nitrogen was seen in dogs
given 5 mkd Cremophor/PEG.
Neither 10%
Solutol/90% PEG , 30% Solutol/70% PEG nor 10%
Cremophor/90% PEG at either dose volume
produced overt toxicity, however using the lower
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2011
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P306
AN 85-DAY REPEAT DOSE INTRADERMAL TOXICITY
STUDY OF AN ENTEROTOXIGENIC E. COLI VACCINE
IN GUINEA PIGS. Godin, C.S.1; O’Dowd, A.2, Maciel,
M.2; Savarino, S.2 1AVANZA Laboratories, LLC,
Gaithersburg, MD; 2Naval Medical Research Center,
Silver Spring, MD
A vaccine against enterotoxigenic E. coli (ETEC) is
being developed to protect travelers and young
children that are at risk from this disease. The
purpose of this study was to determine the
immunogenicity, local skin reactogenicity, and
potential toxicity of the ETEC vaccine candidate,
when administered alone or in combination with an
adjuvant derived from E. coli, to Dunkin Hartley
guinea pigs by the intradermal route on Study Days
1, 22, 43, and 64. Guinea pigs were treated with 100
µL of the vaccine given alone or the adjuvant mixed
with either PBS or the vaccine. Parameters evaluated
included mortality, cageside observations, physical
examinations, body weights, body temperatures,
dermal Draize scores, dose site induration
measurements, gross pathology, organ weights, and
histopathology. Treatment with vaccine with or
without adjuvant had no effect on mortality,
cageside observations, physical examinations, body
weights, body temperature, gross pathology, or
organ weights. Administration of the vaccine alone
resulted in a few observations of mild erythema but
no induration. Administration of the adjuvant
resulted in a dose-related increase in severity of
erythema and edema but the severity appeared to
decrease with repeated dosing. In addition, the
incidence of positive Draize scores appeared to be
lower in those animals that received vaccine in
combination with adjuvant. Administration of
adjuvant alone or in combination with vaccine
resulted in areas of induration following the first
dose that increased with dose level. However, only
animals receiving the adjuvant without vaccine
developed areas of induration at subsequent
intervals. The tested vaccine components all
produced variable inflammation at the inoculation
site that was evident two days post-inoculation but
which had resolved completely by three weeks postinoculation.
Cathy Moore 1 1 Covance Laboratories, Chandler, AZ 2
Covance Laboratories, Chantilly, VA
α-Chlorohydrin (αCH) is reported to produce
spermatotoxicity, however little is known of the
lasting effects of αCH. The purpose of this study was
to evaluate the effects of αCH given orally (p.o.) or
subcutaneously (SQ) on male reproductive
parameters and body weight (BW) and food
consumption (FC) in rats with a 1-week recovery.
Sixty rats > 9 weeks old were randomly divided into
5 groups of 12 and given control (water) or 5, 20 or
40 mg/kg/day αCH p.o. or 40 mg/kg/day αCH SC.
Following treatment (TRT), half the animals were
euthanized. The remaining animals were euthanized
following a 1-week recovery (REC). The right vas
deferens was collected for sperm motility and right
epididymis was collected for sperm count and
morphology.
Mean sperm counts decreased in animals given
40 mg/kg/day αCH p.o. or SQ (TRT~320 million/g;
REC~300 million/g) compared with controls
(TRT=1416 million/g; REC=1630 million/g). Percent
abnormal sperm increased in animals given 40
mg/kg/day αCH p.o. or SQ (TRT>50%; REC~90%)
compared with controls (TRT=0.4%; REC=0.9%). The
percent of sperm with missing tails increased in
animals given 40 mg/kg/day αCH p.o. or SQ
(TRT>50%; REC>90%) compared with controls (TRT
and REC~5%). Body weight was decreased in males
given 40 mg/kg/day αCH p.o. or SQ (TRT~9%, p<0.05;
REC~10%) compared with controls.
This was
reflected in decreased BW gain and FC (~50% and
~80% of controls, respectively) during TRT. REC FC
was similar while REC BW and BW gain were
different between rats given αCH or control.
In conclusion, route of administration of αCH had
similar effects on measured parameters. Rats given
40 mg/kg/day αCH p.o. or SQ with a 1-week recovery
had a higher percentage of abnormal sperm and
sperm with missing tails than rats at the completion
of treatment.
P308
SAFETY
OF
HIGH
MOLECULAR
WEIGHT
POLYETHYLENE GLYCOL (PEG) IN BIOTHERAPEUTICS
-- CASE OF PEGYLATED FVIII
TA McDonald, IA
Ivens, Bayer HealthCare, San Francisco, California
Polyethylene glycol (PEG) molecules have been
linked to protein drugs to alter the kinetics or reduce
the immunogenicity of the protein.
Of the
PEGylated proteins on the market, 4 contain PEG
≥30 kDa -- the largest PEG is a branched 40 kDa PEG.
Several other PEGylated proteins are in clinical
development. No PEG-related systemic toxicity has
P307
EFFECTS
OF
α-CHLOROHYDRIN
WHEN
ADMINISTERED TO MALE Crl:CD(SD) RATS FOR 2WEEKS ORALLY OR BY SUBCUTANEOUS INJECTION
WITH A 1-WEEK RECOVERY
James Ford, Jr.1,
1
1
James Kosco , David Schuette , John-Michael Sauer1,
Jay Albretsen1, Duane Belote1, Lynn Zuwannin2 and
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
been reported for these drugs. BAY 94-9027, a
PEGylated, recombinant FVIII (rFVIII) developed for
hemophilia A, contains a single, 60 kDa PEG to
prolong half-life and therefore efficacy. A clinical
intravenous dose of 50 IU/kg for BAY 94-9027
corresponds to a very low PEG intake of
approximately 3 microgram PEG/kg per dose.
Before clinical trials, potential safety of PEG-FVIII
was evaluated, including any special concerns over
the use of a large PEG molecule. In intravenous
toxicology studies of 60 kDa PEG, no adverse effects
and no histopathological changes were observed up
to and including the highest doses tested: 210 mg/kg
after single dose or 11 mg/kg dosed every other day
for 4 weeks. The dose of 11 mg/kg is more than the
cumulative clinical lifetime dose of 60 kDa PEG
received from BAY 94-9027. A literature evaluation
of the safety and elimination of PEGylated proteins
(PEG ≥30 kDa) is provided, and this information is
consistent with the lack of toxicity seen for 60 kDa
PEG here.
The data indicate that long-term
treatment with BAY 94-9027 will not result in PEGrelated systemic toxicity.
determining toxic doses before committing to an in
vivo study. Previous studies by Pessina et al. (Tox
Sci. 2003. 75:355-367) indicate that for many drugs,
human maximum tolerated doses (MTDs) can be
predicted by adjusting mouse-derived MTDs.
However, some studies indicate that significant
differences exist among human, canine, rat and
mouse
hematosensitivities
to
certain
pharmaceuticals/toxins, with human cells showing
higher sensitivity to the toxic effects of the
compounds studied. Consequently, information
from comparative CFC assays may be of great
importance before entering clinical trials. Recent
studies were conducted using chemotherapeutics
and an environmental toxin to evaluate their effects
on myeloid (CFU-GM) progenitors acquired from
human, canine, rat and mouse bone marrow. The
resulting data show that while all tested compounds
displayed a dose-dependent toxic effect on colony
growth, each compound demonstrated species
specificity. While conditions in the human body
cannot be completely reproduced in vitro, CFC
assays can be used to help bridge the gap between
high throughput screening technologies and in vivo
studies.
400 series – Special Studies
P401
CHARACTERIZATION
OF
BASELINE
CARDIOVASCULAR FUNCTION IN THE CONSCIOUS,
FREELY-MOVING, JUVENILE NON-HUMAN PRIMATE
Ali S. Faqi, John C. Resendez and Theodore J. Baird,
MPI Research, Mattawan, MI 49071
Most nonclinical/clinical drug safety assessments
are conducted in developmentally mature subjects,
which may not represent the most appropriate test
sample for evaluating compounds with pediatricspecific indications. When children are the primary
population, age-appropriate studies in juvenile
animals are important for assessing direct toxic or
developmental risks. With emerging trends in
biologics, the necessity of conducting juvenile
toxicology studies in non-human primates (NHP) will
likely increase. The purpose of this study was to
characterize
the
postnatal
developmental
progression of key cardiovascular safety endpoints in
approximately 7-14 month old juvenile NHPs. To
assure a comprehensive evaluation, utilizing
continuous data sampling procedures without
complications associated with chemical or physical
restraint; eight recently weaned cynomolgus
macaques were surgically instrumented with
radiotelemetry transmitters to measure systemic
arterial pressures and body temperature, and to
record a standard electrocardiogram (ECG). A
P400
TOXICITY ON BONE MARROW PROGENITORS FROM
DIFFERENT SPECIES: AN IN VITRO TEST TO PREDICT
MYELOSUPPRESSION AND NEUTOPENIA
Elaine
Lau1, Mary Huber1, Diane Monteith1, Annie Tam1,
Chista Farzim1, Allen Eaves1,2 and Jackie Damen1.
1
STEMCELL Technologies Inc. Vancouver, BC, Canada,
2
Terry Fox Laboratory, BC Cancer Agency,
Vancouver, BC, Canada
The use of hematopoietic stem and progenitor
cells in colony-forming cell (CFC) assays to test the
effects of environmental toxins, chemotherapeutics,
and other drug classes has been well documented.
These assays have been used to screen compounds
for toxicity before the initiation of costly clinical
trials and as a tool to help determine maximum
tolerated doses (MTDs). While several assays exist
for studying different progenitor types, a great deal
of research has focused on use of the colony forming
unit-granulocyte/macrophage (CFU-GM) assay as a
measure
of
the
progenitors
of
the
granulocytic/monocytic lineage. In fact, this assay
has been optimized and validated for use as an in
vitro predictor of acute-onset neutropenia by
potential hematotoxicants. Choice of species is an
important consideration when testing a new drug.
Mouse CFC assays can be an important tool for
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
pressure-sensitive
catheter
was
introduced
femorally and positioned within the descending
aorta, and bipolar electrode implanted to record a
Lead II ECG. To facilitate long-term vascular access,
a femoral venous catheter was implanted and
connected to a subcutaneous vascular access port.
Heart rate, blood pressure, body temperature and
the ECG were collected according to a bi-weekly
schedule using PoNeMah (Ver 4.1) software.
Telemetry data, including standard ECG reference
intervals (RR, PR, QRS, QT, QTc), heart rate, blood
pressure, body temperature will be presented and
compared to a reference historical control dataset
previously collected from a large sample of adult
NHP subjects (Gauvin et al., 2006, J Pharmacol
Toxicol Methods 53:140-51).
The nature and
putative bases for observed differences in baseline
values for these physiological variables between
adult and developing juvenile animals will be
discussed.
profile in CDDP-treated animals differed from that
seen in DOX-treated animals, consistent with a
mechanistic link between biomarker and type of
injury.
These results suggest differences in biomarker
profiles are indicative of direct and indirect PCT
damage. The dose-related onset and severity of
injury also matched well with temporal biomarker
responses in both models.
P403
MINI)PIGS
IN
DEVELOPMENTAL
AND
REPRODUCTIVE
TOXICITY
((DART)
STUDIES
Ganderup, NC (1) & Navratil, N (2) 1: Ellegaard
Göttingen Minipigs, Denmark, ncg@minipigs.dk. 2:
Marshall
BioResources,
USA,
nnavratil@marshallbio.com.
Reproductive studies in the context of safety
assessment of new medicines are performed
routinely in a rodent and the rabbit. However, in
cases where the rabbit may not be suitable as the
non-rodent model, the minipig may be a suitable
alternative, and should be considered before
utilising non-human primates (NHPs).
This poster has three components:
1) Male and female reproductive characteristics,
including embryonic development, and a
comparison with other commonly used species.
2) Data about the nature and frequency of
congenital malformations and abnormalities
observed in the Göttingen Minipig production
herd. Although such data cannot be a substitute
for data obtained from control groups, this
information can be valuable when interpreting
DART studies.
3) A literature review on the use of pigs and
minipigs in teratology studies provide additional
knowledge about the species in this context.
Pros and cons of minipigs in the context of DART
studies will also be presented.
Minipigs have been used for regulatory segment II
studies and should be considered as a relevant
alternative to the rabbit (if unsuitable). The minipig
should be considered before using NHPs.
P402
LONGITUDINAL
PROFILES
OF
BIOMARKERS
ASSOCIATED WITH NEPHROTOXICITY IN RATS
TREATED WITH DOXORUBICIN OR CISPLATIN
J. Smith, S. Nodop Mazurek, K. Lincoln, F. Pack, A.
Mineo, A. Muthukumarana, A. Hudak, P. Harrison, R.
Fryer,
J.
Phillips,
Boehringer-Ingelheim
Pharmaceuticals, Inc. Ridgefield CT
Several renal injury biomarkers can outperform or
add value to conventional serum BUN and creatinine
(sCr) in rat toxicology studies. Here we report daily
measurement of exploratory urinary biomarkers of
renal function, tissue injury and leakage during 15
day studies in rats treated with doxorubicin (DOX),
or cisplatin (CDDP). Biomarker results are compared
to terminal histopathology and serum chemistries
(pretest, d7 and terminal).
Renal histopathology showed dose-dependent
glomerular, proximal convoluted tubule (PCT) and
collecting duct damage in DOX-treated animals and
PCT necrosis in CDDP-treated animals. Serum BUN
and sCr were unchanged compared to vehicle
controls in all treatment groups. In contrast to BUN
and sCr, albuminuria increased in DOX-treated
animals compared to vehicle (high dose at d4 and
low dose at d7). Albumin increases were followed by
changes in other functional biomarkers (d6-7 high
dose, d9-10 low dose) such as 2 microglobulin and
cystatin C which were then followed by inducible
injury marker responses (d8-10 high dose, d13-15
low dose) such as KIM-1, lipocalin-2 and clusterin.
Biomarker responses matched well with type and
incidence of histopathology findings. Biomarker
P404
ACUTE CARDIOVASCULAR EFFECTS IN DOGS
TREATED INTRAVENOUSLY WITH CAPTISOL®
Vincent L. Reynolds1, Derek J. Leishman1, Bradley W.
Main2, Christine Clawson2, and Courtney R. Burch2
1
Eli Lilly and Company, Indianapolis, IN; 2Covance
Laboratories, Greenfield, IN
Captisol® (β-cyclodextrin sulfobutyl ether sodium
salt) is an excipient used in toxicology studies to
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
solubilize and stabilize test materials. To evaluate
the potential for vehicle effects on cardiovascular
(CV) parameters with Captisol®, beagle dogs (n = 2
females/group; instrumented with left ventricular
and aortic pressure sensors) received i.v. doses (6
mL/kg as 1- to 2-minute bolus doses via catheters
placed in the cephalic vein) of saline (0.9%) or
Captisol® (12% in purified water, pH 6). CV
parameters (systolic, diastolic, mean arterial, and
pulse pressure, dP/dtmax, and heart rate) and body
temperatures were measured 30 min pre-dose
through 3.5 hrs post-dose. The dogs were placed in
slings for the duration of CV data collection.
Noteworthy clinical signs occurred only with
Captisol® and included tremor, loss of consciousness,
loss of muscle control, and/or aggression. A
transient increase in heart rate occurred with both
saline and Captisol® that persisted only during the 1to 2-minute dosing interval. With saline, there were
no appreciable effects on blood pressure or
inotropy. Captisol® caused a biphasic blood pressure
response, with an initial increase followed by a
severe (>50%) transient decrease that necessitated
the i.v. administration fluids to 1 dog as rescue
therapy. A decrease in left ventricular inotropic state
was noted in the dogs treated with Captisol®.
Because of the concomitant decrease in blood
pressure, it was not possible to determine if the
decreased inotropy was a direct effect or secondary
to a decrease in afterload.
Neural tube, abdominal wall, and tail anomalies
were observed in the GD 9 group, and cleft
lip/palate in the GD 9, 10, and 11 groups.
Cardiovascular, reproductive, liver, renal, adrenal,
spleen, and diaphragm anomalies were observed
with the overall group incidence in the order
GD 9>10>11>12. The most common anomalies were
great vessel transposition, absent aortic arch,
ectopic testes/ovaries, abnormal liver lobation,
absent diaphragm; and supernumerary kidney
(GD 11>9). Axial skeletal development was markedly
affected in the GD 9 group with numerous skull, rib,
sternebral, and vertebral anomalies, most notably
absent and fused structures. In conclusion, ASA
administration to rats during major organogenesis
resulted in embryolethality and/or malformations,
which is consistent with the published literature. A
single oral dose on GD 9 produced the most severe
effects, followed by GD 10, and to a lesser extent
GD 11 and 12.
P406
A 13-WEEK NONCLINICAL PHOTOSAFETY STUDY IN HAIRLESS
MICE TO CHARACTERIZE THE BIOMARKER RESPONSES OF HIGH
DOSES OF ULTRAVIOLET RADIATION (UVR) AND 8METHOXYPSORALEN (8-MOP) T Coston1, D Learn1, C
Sambuco, D Forbes2, S Johanssen3, C Guenther3 1
Preclinical Services, Charles River Laboratories,
Horsham PA
2
Toxarus Inc., Malvern PA, 3 Preclinical
Development, Intendis GmbH, Berlin Germany
The purpose of the presented study was to
characterize the response of biomarkers for
photocarcinogenicity of high doses of simulated
sunlight (UVR) and the combination of 8Methoxypsoralen (8-MOP) and UVR. Both exposure
to UVR alone and 8-MOP+UVR are known to
enhance photocarcinogensis in mice and humans,
and were chosen to evaluate biomarker response as
a surrogate for skin tumor development in hairless
mice. The employed biomarkers included apoptosis
as determined by sunburn cell production, cell
proliferation as determined by incorporation of
bromo-deoxyuridine
during
DNA
synthesis,
epidermal cellularity and thickness, and dermal
inflammatory infiltration. Clinical observations, skin
reaction observations, body weights and skin
thickness measurements were recorded. Six groups
of albino hairless mice were treated over 13 weeks
as follows: untreated control, UVR low dose (600
Robertson-Berger Units/week (RBU/wk)), UVR mid
dose (1200 RBU/wk), UVR high dose (2400 RBU/wk),
8-MOP low dose + UVR low dose, 8-MOP high dose +
UVR low dose. Low dose 8-MOP formulation
P405
DEVELOPMENTAL TOXICITY OF ACETYLSALICYLIC
ACID IN RATS.
E. Mylchreest, K.S. Gilbert, C.B
Cagle, Southern Research, Birmingham, AL.
A positive control study was conducted with
acetylsalicylic acid (ASA) to support training on
identification of fetal anomalies. Rats (10-12/group)
were administered a single dose of ASA orally by
gavage at 0 or 500 mg/kg (5 mL/kg in 0.2%
methylcellulose) on gestation day (GD) 9, 10, 11, or
12. A laparohysterectomy was performed on GD 21
and fetuses were weighed and examined for
external, visceral, and skeletal anomalies.
Postimplantation loss was increased in the GD 9 and
10 groups (mean of 54.2% and 13.3% vs. 3.5% in
controls). In the GD 9 group, this was due to
increased dead fetuses (mean of 1.0 vs. 0 in
controls), early resorptions (6.3 vs. 0.6 in controls),
and late resorptions (0.6 vs. 0 in controls); but was
due to increased early resorptions in the GD 10
group (2.0 vs. 0.6 in controls). There was a resultant
decrease in the number of live fetuses in the GD 9
and 10 groups (7.0 and 12.8 vs. 15.4 in controls).
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
concentration was 0.01 mg/mL (100µL/25 cm²) in
Weeks 1-8 and 0.1 mg/mL in Weeks 9-13. High dose
8-MOP formulation concentration was 0.1 mg/mL in
Weeks 1-8 and 1 mg/mL in Weeks 9-13. UVR caused
a dose-related increase in all biomarkers. The
combination of 8-MOP and UVR had only minimal
effects on biomarkers at the low dose of 8-MOP,
whereas the effects of high dose of 8-MOP with UVR
were generally greater than UVR alone. Skin reaction
observations and skin thickness measurements
generally correlated well with the biomarker results.
The findings indicate that the evaluated biomarkers
were clearly affected by two stimuli known to
enhance photocarcinogenesis: simulated sunlight
exposure alone; and a phototoxic regimen (8-MOP +
UVR).
time spent freezing, decreased percent time spent
freezing and increased motion index over each test
session. Therefore, these results validate that the
methodologies and testing procedures described at
WIL Research.
P408
DRUG DISCRIMINATION ASSESSMENTS WITH
MORPHINE, TRAMADOL, AND OXYCODONE IN THE
ADULT MALE RAT
Jonathan D. Toot, Melissa J.
Beck, Donald G. Stump, Michelle L. Hackman and
Mark D. Nemec. WIL Research Laboratories, LLC.
1407 George Road, Ashland, OH, 44805-8946
The objective of this study was to assess the drug
discrimination (DD) testing paradigm utilized at WIL
Research Laboratories, LLC, using morphine as the
reference compound with test drug substitutions
including
tramadol hydrochloride, oxycodone
hydrochloride and morphine sulfate in the rat within
the scope of the European Medicines Agency
guidelines. The animals used for this study consisted
of adult Sprague Dawley males (n=12-16),
approximately 8 weeks of age at initiation of training
and testing. Rats were first trained by food pellet
reinforcement under a fixed ratio (FR) 20 schedule to
discriminate between the compound associated
levers when administered the reference compound
(RC), morphine (5.6 mg/kg), or the vehicle control
(saline) via intraperitoneal injection approximately
30 minutes prior to the drug discrimination session.
Discrimination testing was conducted following
compound substitution of the following test drugs:
tramadol at 1.0, 10, 20 and 30 mg/kg; oxycodone at
1.0, 5.0, 10 and 20.0 mg/kg; and morphine at 0.3,
3.0, and 9.0 mg/kg. Using this paradigm, the first 20
lever presses were reported as the relative percent
of RC lever selection. The results of this study
showed RC lever selection (>80%) for substitution
with oxycodone (5.0 mg/kg) and morphine (5.6 and
9.0 mg/kg). Tramadol resulted in intermediate levels
of substitution over the dose levels administered,
with RC lever selection between 10 and 60%. Also,
the remaining dosage levels for each compound did
not fully substitute (RC level selection below 25%) or
substitution assessment criteria was not achieved
(failure to complete the first FR) over the high dose
levels administered. The DD testing paradigm was
able to characterize the selected compounds for
their known discriminative potential. Therefore,
these results validate that the methodologies
described at WIL Research are in accordance with
the EMEA guidelines.
P407
CONTEXTUAL FEAR CONDITIONING ASSESSMENT
WITH SCOPOLAMINE IN THE ADULT MALE RAT
Jonathan D. Toot, Lynette M. Vana, Matt R. Bennett,
Melissa J. Beck, Donald G. Stump and Mark D.
Nemec. WIL Research Laboratories, LLC. 1407
George Road, Ashland, OH, 44805-8946
The objective of this study was to assess the
modified contextual fear conditioning (CFC) testing
paradigm utilized at WIL Research Laboratories, LLC,
using scopolamine hydrochloride as the positive
control agent . The animals used for this study
consisted of adult Long Evans males (n=10/group),
approximately 12 weeks of age at initiation of
testing. The CFC assessments took place over 2 days,
with the initial training on Day 1, followed by cue
and contextual testing on Day 2. Animals were given
an intraperitoneal injection of either scopolamine
(20 mg/kg) or vehicle (saline) approximately 15
minutes following the completion of training.
Training on Day 1 consisted of a single 3 minute
session in which a 2 second 0.5 mA foot shock
(aversive stimulus) was paired with an 85 dB
auditory tone (neutral stimulus). Context Testing on
Day 2 consisted of a single 5 minute session without
the aversive and neutral stimuli. Cue testing on Day
2 consisted of single 6 minute session with a
modified floor overlay and presentation of the
neutral stimulus. The parameters included freeze
count, percent time freezing, time spent freezing,
and average motion index were recorded and
analyzed quantitatively. As expected, there were no
differences between either treatment groups during
training on Day 1. However, both context and cue
testing on Day 2 indicated impaired performance in
the scopolamine versus vehicle treated group with
an increased number of freeze counts, decreased
99
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P409
NEUROBEHAVIORAL ASSESSMENTS OF STARTLE
RESPONSE, MOTOR ACTIVITY, AND LEARNING/
MEMORY IN ADULT RATS
Jonathan D. Toot,
Michelle L. Pershing, Melissa J. Beck, Donald G.
Stump, Mark D. Nemec WIL Research Laboratories,
LLC. 1407 George Road, Ashland, OH, 44805-8946
The purpose of this study was to evaluate the
ability of Kinder Scientific Startle Response Chamber,
Kinder Scientific Motor Activity Chamber and
Complex water T-maze to detect decreases and
increases (as appropriate) in each endpoint following
treatment with various CNS acting compounds in
adult male and female Sprague-Dawley Crl:CD rats.
For each neurobehavioral assessment and
compound, separate subsets of 20 rats/sex were
assigned to each control and treatment group. To
assess decreased auditory startle response,
chlorpromazine was administered (SQ) at dosage
levels of 0, 2 and 10 mg/kg on PND 60. For increased
auditory startle response, amphetamine was
administered (IP) at dosage levels of 0, 1.0 and 5.0
mg/kg on PND 60. To assess decreased motor
activity, haloperidol was administered (IP) at dosage
levels of 0, 0.05, 0.1, and 0.5 mg/kg prior to
behavioral testing on PND 61. For assessments of
increased motor activity, amphetamine was
administered (IP) at dosage levels of 0, 1.0 and 5.0
mg/kg on PND 61. For impaired learning/memory
performance, scopolamine was administered (IP)
twice daily at dosage levels of 0, 0.5, 1.5 mg/kg from
PND 62-68. The results of this neurobehavioral
study in adult rats found that treatment on PND 60
with chlorpromazine resulted in a dose dependent
decrease in the maximum force across all blocks of
trials, with an increase in the time to reach the
maximum force. Amphetamine-treated males and
females exhibited an increase in the mean maximum
response force on PND 60.
Treatment with
haloperidol caused a dose-dependent decrease in
locomotor activity (total activity counts and
ambulatory counts) for both male and female rats at
PND 61. Amphetamine treatment resulted in an
increase in locomotor activity (mean total and
ambulatory activity) in male and female rats on PND
61. Scopolamine administration from PND 62-68
resulted in a generalized and dose dependent
impairment, with an increased time to escape the
maze and increased error number. Therefore, these
results validate that the methodologies and testing
procedures described at WIL Research.
P410
NONCLINICAL SAFETY EVALUATION OF XOMA 3AB,
A NOVEL TRIPLE MONOCLONAL ANTIBODY DRUG
PRODUCT TARGETING BOTULINUM TOXIN TYPE A,
IN SPRAGUE-DAWLEY RATS
K Meyer1, H Ng2, T
2
2
Parman , A D’Andrea , T Harrison2, C Green2, J Ma1, L
Cao1, B Shimizu1, K Der1, J Mirsalis2. XOMA (US) LLC1,
Berkeley, CA; SRI International2, Menlo Park, CA.
XOMA 3AB is being evaluated for the treatment
and prevention of botulinum toxin type A (BoNT/A)
poisoning. XOMA 3AB is composed of an equimolar
mixture of three human or humanized IgG1
monoclonal antibodies (mAb), referred to as NX01,
NX02 and NX11, that target unique non-overlapping
regions on BoNT/A. These antitoxin mAbs bind to
BoNT/A resulting in rapid clearance of the toxin from
the systemic circulation.
Nonclinical safety
evaluation pharmacokinetics (PK) and toxicology
studies were conducted in Sprague-Dawley rats to
support the clinical development of XOMA 3AB. The
PK of XOMA 3AB was evaluated in rats for 71 days
following a single intravenous injection at dose levels
0.1, 1 and 10 mg/kg. XOMA 3AB was administered
weekly for five weeks by intravenous injection at
doses up to 50 mg/kg and by intramuscular injection
at a dose level of 3 mg/kg for toxicology assessment.
Parameters evaluated included clinical observations,
food consumption, body weights, clinical pathology,
ophthalmology,
urinalysis,
macroscopic
and
microscopic evaluation. Bioanalytical assays were
developed using an electrochemiluminescence (ECL)
format to measure the individual mAbs in rat serum.
An ECL assay was also developed to measure total
anti-drug antibodies to XOMA 3AB. The results show
that NX01, NX02 and NX11 have similar PK profiles
and demonstrate a dose proportional bi-exponential
decline in initial and terminal half-lives, clearance
and volume of distribution. The half-lives of NX01,
NX02 and NX11 ranged from 12.4 to 17.2 days.
Animals with anti-drug antibodies showed increased
clearance of XOMA 3AB from the serum. There were
no toxicologically significant findings related to
administration of XOMA 3AB to rats. The noobservable-adverse-effect level (NOAEL) following
intravenous administration was ≥ 50 mg/kg, the
highest dose tested.
In summary, the three mAb components of XOMA
3AB show similar PK profiles following IV and IM
injection, and there were no drug-related adverse
toxicological findings in rats.
This project has been funded in whole or in
part with federal funds from the NIAID, NIH,
DHHS contract numbers HHSN266200600008C and
HHSN266200600011C.
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P411
ABSENCE OF GENOTOXICITY BY THE ANTISENSE
OLIGONUCLEOTIDE PRO044.
Yolanda PonsteinSimarro Doorten and Sjef J. de Kimpe, Prosensa
Therapeutics BV, 2333 CH Leiden, The Netherlands
PRO044 is a 2’-O-methyl phosphorothioate RNA
antisense oligonucleotide (AON) product that is
currently being developed for the treatment of
Duchenne Muscular Dystrophy (DMD), a lethal
orphan disease for which currently no therapy exists.
The fundamental cause of this disease is mutations
in the DMD gene leading to out of frame transcripts
for the muscle protein dystrophin. AON-induced
exon skipping of exon 44 in the human dystrophin
pre-mRNA results in the restoration of the reading
frame and might result in a (partially) functional
dystrophin protein. The mutagenic and clastogenic
potential of PRO044 was assessed using in vitro tests
in bacteria and mammalian cells and an in vivo
rodent assay. The bacterial reverse mutation assay
(i.e. Ames test using Salmonella typhimurium TA98,
TA100, TA102, TA1535 and TA1537) showed that
PRO044 has no mutagenic activity at concentrations
up to 10.000 µg per plate, in the presence or
absence of an in vitro metabolic activation system
(S9-mix). The Chinese hamster ovary (CHO)
chromosomal aberration assay showed that PRO044
did not induce structural aberrations in the presence
or absence of S9-mix, up to the maximum tested
concentration of 5.000 µg/mL. In addition, PRO044
didn’t induce any polyploidy nor gave indications of
mutagenic properties in the presence or absence of
S9-mix at 5.000 µg/mL. In the in vivo micronucleus
assay, no genotoxic effect was observed in the bone
marrow of mice following repeated subcutaneous
administrations at three PRO044 dose levels (i.e. 80,
200 and 500 mg/kg on days 1, 3, 5 and 8) resulting in
a weekly exposure of 320, 800 or 2.000 mg/kg. In
conclusion, results from the above mentioned tests
demonstrate that PRO044 is not mutagenic nor
clastogenic which confirms the uniform consensus
that 2’O-methyl AONs do not exert mutagenic nor
clastogenic effects.
P412
COMPLEMENT ACTIVATION AFTER TREATMENT
WITH ANTISENSE OLIGONUCLEOTIDES IN VIVO AND
IN VITRO.
Yolanda Ponstein-Simarro Doorten,
Ingrid G.M. Kolfschoten, Suzanne Bijl and Sjef J. de
Kimpe, Prosensa Therapeutics BV, 2333 CH Leiden,
The Netherlands.
One of the class toxicities of phosphorothioate
antisense oligonucleotides (AONs) is the activation
of the complement pathway shown in non-human
primates. Rapid infusion of high levels of AONs can
result in clinical, hematologic, and hemodynamic
disturbances. This condition has been linked to the
activation of the alternative complement pathway,
since complement split products C3a and Bb were
shown to increase in plasma, which may activate
neutrophils and macrophages. In order to assess the
predictive value of in vitro analysis of the levels of
the complement split factors C3a and Bb, monkey
plasma was incubated with AONs PRO044 and
PRO046 (containing a full 2’O-methylated backbone)
and compared to in vivo data obtained with
cynomolgus monkeys treated with these AONs. The
mentioned AONs are currently developed by
Prosensa for the treatment of Duchenne Muscular
Dystrophy (DMD), by means of exon skipping. As a
positive control, monkey plasma was also incubated
with cobra venom factor (CVF). In vitro, levels of C3a
and Bb increased upon exposure to the AONs and
CVF. In vivo, a similar activation pattern of the
alternative pathway was found for the tested AONs.
These results indicate that an in vitro screening of
the activation of complement pathway by AONs can
be used to predict in vivo complement activation in
monkeys. Activation of the alternative pathway by
AONs was also tested in human plasma. PRO044 did
not activate the alternative complement pathway,
while PRO046 and CVF showed an increase in the
levels of complement split factors C3a and Bb. In
contrast to PRO044, PRO046 has been shown to
form multimers, which seems to be a stimulating
factor for complement activation. These results
substantiate that the activation of the alternative
pathway by 2’O-methyl AONs is sequence and
species specific and that monkeys are more sensitive
than humans.
101
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P413
SAFETY PHARMACOLOGY ASSSESSMENT OF THE
ANTISENSE OLIGONUCLEOTIDE PRO044. Yolanda
Ponstein-Simarro Doorten and Sjef J. de Kimpe,
Prosensa Therapeutics BV, 2333 CH Leiden, The
Netherlands
PRO044 is a 2’-O-methyl phosphorothioate RNA
antisense oligonucleotide (AON) product that is
currently being developed for the treatment of
Duchenne Muscular Dystrophy (DMD). The aim of
PRO044 is to restore the human dystrophin premRNA reading frame by means of exon skipping,
resulting in a (partially) functional dystrophin
protein. In order to identify potential signals that
could subsequently be monitored in human clinical
trials, PRO044 was tested in several safety
pharmacology studies. The overt central and
peripheral nervous system effects were assessed in
mice, by means of the so-called IRWIN test. Actions
on respiratory and cardiovascular systems were
tested in the in vitro electro-conductivity (so-called
hERG) assay and an in vivo study using non-human
primates. In the IRWIN test, repeated subcutaneous
administrations of PRO044 at dose levels of 50, 100
and 200 mg/kg on test days 1, 3, 5 and 8, did not
result in any effect on neurobehavioral functional
assessments reflecting normal central and peripheral
nervous system activity. In the hERG assay, Chinese
Hamster Ovary (CHO) cells stably expressing the
potassium channel hERG were exposed to PRO044
and the channel tail current was measured by means
of the patch-clamp technique. No effects on the
channel tail current were observed after exposure to
PRO044 concentrations of 15, 75 and 150 μM,
corresponding to 0.11, 0.55 and 1.09 mg/ml,
respectively. Cardiovascular and respiratory effects
potentially induced by PRO044 were investigated in
a sub-chronic repeated dose study in monkeys. No
changes in ECG parameters, including QT intervals
up to 13 weeks at a maximum dose of 54 mg
PRO044/kg/week were observed. In conclusion, no
PRO044-induced effects were observed in the tested
battery of safety pharmacology studies.
D--tocopheryl
polyethylene
glycol
1000
succinate (TPGS) is a valuable excipient for
hydrophilic and lipophilic drug vehicles because it is
an emulsifier, solubilizer, and absorption enhancer.
However, TPGS has been said to affect (mask) drug
effects because of potential anti-cancer/anti-oxidant
effects. Tocopherol succinate (TS), the vitamin E
(VitE) form in TPGS, has anti-cancer/anti-oxidant
effects in vitro and when injected into tumors or
given intraperitoneally (IP) in animal cancer models.
When TPGS is administered orally (PO), TS is
hydrolyzed in the gastrointestinal tract to tocopherol
(TOC), the less active VitE. The goal of this study was
to evaluate TS exposure after PO TPGS, 2 groups of
rats (N= 10/group) were given different TPGScontaining vehicles for 7 days: 60% polyethylene
glycol 400 (PEG-400)/40% TPGS (550 mg/kg/d TS) or
aqueous 75% 0.1M phosphate buffer/15% PEG400/5% polyvinyl pyrrolidone/5% TPGS (70 mg/kg/d
TS). Two control groups received daily PO PEG-400
(no VitE supplement) or IP TS (100 mg/kg, days 1, 3,
5, 7). On Day 8, plasma, liver, kidney, brain, and
adrenal TS and TOC concentrations were measured
by LC-MS. Plasma and tissue TS and TOC were not
significantly increased after PO TPGS vehicles and TS
was poorly absorbed when given PO. These data
support the conclusion that VitE concentrations are
not significantly increased in rats following PO TPGS,
even at a TS dose of 550 mg/kg/d. Thus, TPGScontaining drug vehicles are unlikely to mask drug
effects in PO toxicity studies.
500
series
Toxicology
–
Environmental
P500
TOXICITY OF MANEB AND MANCOZEB PESTICIDES
CONTRIBUTING TO RAT PHEOCHROMOCYTOMA
CELLULAR
DEATH
AND
THE
POTENTIAL
NEUROPROTECTIVE EFFECTS OF POLYPHENOLS
AGAINST THESE INSULTS
Marcela Velasco,
Graduate Student, John Jay College of Criminal
Justice
Parkinson’s Disease is the second most common
neurodegenerative disorder in the United States. Its
pathology is characterized by a selective loss of
pigmented neurons in the substantia nigra resulting
in dopamine depletion. Pesticides causing chemical
alterations that lead to neuronal apoptosis will also
hinder the production of this neurotransmitter,
possibly resulting in Parkinsonism or other diseases
such as Alzheimer’s and Attention Deficit
P414
DOES ORAL D--TOCOPHERYL POLYETHYLENE
GLYCOL 1000 SUCCINATE AFFECT DRUG TOXICITY?
RW Lange, TW Salcedo, M Donegan, RK Perrone, RT
Bunch, TP Sanderson, and MH Davies Bristol-Myers
Squibb Drug Safety Evaluation, Bioanalytical
Research, and Drug Product Science and Technology;
Mt.Vernon, IN, New Brunswick and Lawrenceville,
NJ, and Wallingford, CT
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Hyperactivity Disorder. The present study
investigated the effects of Maneb and Mancozeb
pesticides in PC12 cells, which resemble the
chemistry and physiology of dopaminergic neurons.
Cells were treated with a 20 M Maneb and 20 M
Mancozeb for 1 hour. Using MTT toxicology assay
Maneb and Mancozeb treated cells showed a
decrease in mitochondrial function of 24.64% and
21.56% respectively. These PC12 groups were then
treated with Polyphenols (10 M), known to be
potent ROS scavengers, in order to study potential
neuroprotective effects. No PC12 cell survival was
observed in affected cells treated with Polyphenols
suggesting that Maneb and Mancozeb do not act as
oxidative stressors or that neuron death results from
multiple mechanisms in which oxidative stress is not
the driving event. DNA fragmentation was also
examined using comet-assay. DNA breakage was
evident in Maneb and Mancozeb exposed groups,
demonstrating that these neurotoxins are capable of
causing considerable genetic damage. Findings
indicate that both pesticides do in fact disrupt PC12
mitochondrial function and cause DNA damage. This
study confirmed the neurotoxicity of Maneb and
Mancozeb adding to their relevance in the
pathogenesis of neurodegenerative diseases.
Hemoglobin, Hematocrit, MCV, RBC count, MCH and
MCHC of patients decreased (p<0.001) and fasting
blood glucose increased (P=0.027) significantly.
There was no correlation between BLCs and hematobiochemical indices. Conclusion: Garlic tablets
showed therapeutic effects in patients with chronic
occupational lead poisoning.
P502
MORPHOLOGIC AND PROTEIN ALTERATIONS IN
FISHER RAT TRACHEA EXPOSED TO MAINSTREAM
*
CIGARETTE SMOKE
Charleata A. Carter, *Manoj
#
Misra and Robert R. Maronpot. *A.W. Spears
Research Center, Lorillard Tobacco Company,
Greensboro, NC 27405 and #EPL, Inc, Research
Triangle Park, NC 27709 USA
A short-term 5-day nose-only smoke exposure
study was conducted in Fisher 344 rats to identify
smoke-induced tracheal protein changes. Groups of
10 male and female 5 wk old rats were assigned to 1
of 4 exposure groups. Animals received filtered air,
or 75, 200 or 400 mg total particulate matter
(TPM)/m3 of diluted 3R4F Kentucky reference
cigarette mainstream smoke. Exposures were
conducted for 3 hrs/day, for 5 consecutive days. Half
of the tracheal tissue was processed for pathology,
and the other half frozen immediately for
proteomics. We hypothesized that smoke activated
tracheal inflammatory and stress-induced pathways.
Mucosal epithelial toxicity from the inhaled material
was evidenced by cilia loss in smoke-treated animals.
Tracheal changes in females were more severe than
in males. Mucosal atrophy occurred in females in
the 200 mg TPM/m3 group. In the 400 mg TPM/m3
group mucosal epithelial hyperplasia was evident,
but was more severe in females. Tracheal lysates
from control vs. treated animals were screened for
800 proteins using antibody-based microarray
technology and subsequently the 18 most changed
proteins evaluated by Western blot. Tracheal
proteins expressed at high levels that were markedly
increased or decreased by smoke treatment
depended on dose and gender and included: caspase
5, ERK 1/2, p38, protein phosphatase 2C (PP2C/ ),
protein phosphatase 6 catalytic subunit (PP6C) and
pyruvate kinase, muscle (PKM2). Thus, smoke
affected protein pathways include stress,
inflammation, tumor suppression, cell cycle control,
cell proliferation and survival, apoptosis, and
transformation. Inflammatory protein changes
occurred with proteomics and pathology. Changes in
identified proteins affected by smoke exposure may
induce functional tracheal changes and could serve
P501
EFFECTS
OF
GARLIC
ON
BLOOD
LEAD
CONCENTRATIONS AND HEMATOLOGICAL AND
BIOCHEMICAL INDICES IN CAR BATTERY WORKERS
Sina Kianousha, Mahdi Balali-Mooda, Seyed Reza
Mousavia, Valiollah Moradia, Mahmoud Sadeghia,
Bita Dadpoura a. Medical Toxicology Research
Center, Faculty of Medicine, Mashhad University of
Medical Sciences, Mashhad, Iran.
Introduction: Previous studies on animals have
revealed that garlic (Allium sativum) is effective in
reducing blood and tissue lead concentration. In this
study, we investigated the effects of garlic on lead
poisoning as well as hematological and biochemical
parameters. Methods: After coordination and
obtaining informed consent, clinical data, blood lead
concentrations (BLC), hematological and biochemical
indices of 59 workers at a car battery industry were
recorded. All patients were treated by Garlet tablets
(garlic powder tablets; 400 mg; 3 times daily) for 4
weeks. Clinical and laboratory tests were performed
again on 14th day post-treatment. Results: Finally,
38 patients completed treatment. Irritability (P=
0.031), headache (P=0.028) and decreased DTRs
(P=0.019) improved significantly following treatment
with garlic. BLCs reduced significantly (P=0.002) from
426.32 ± 185.12 to 347.34 ± 121.05 µg/dL.
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
as early indicators of tracheal damage and
associated disease.
rat. The exposure of rats to dimethoate for 30 days
promoted oxidative stress with an increase in
thiobarbituric acid reactive substances (TBARS) and a
decrease in glutathione (GSH) level as compared to
control. Moreover, the activities of liver antioxidant
enzymes like GPx, GST, GR, SOD and CAT were also
diminished by oxidant damage. Treatment with
vitamin C significantly improves the liver damage
from the oxidative stress caused by dimethoate and
shifts the trend towards the normal status. In
conclusion, vitamin C can be very effective in
reducing liver injury and in overcoming oxidant
damage caused by environmental stressors as
pesticides.
P503
DEVELOPMENT OF AN IN VITRO WHOLE SMOKE COCULTURE MODEL
OF
HUMAN
SMOKING
CONDITIONS Manoj Misra and William Polk. A.W.
Spears Research Center, Lorillard Tobacco Company,
420 N. English Street, Greensboro, NC 27405, USA.
The initiation of cigarette smoking related lung
damage in both acute and chronic exposure
conditions is associated with inflammation in
smokers’ lung concomitant with the recruitment of
inflammatory cells to sites of airway injury. We
developed a novel in vitro cell system to model
conditions related to smoke-exposed human lung by
exposing normal human lung epithelial cells (BEAS2B) co-cultured with human macrophage
inflammatory cells (U937) to mainstream cigarette
smoke. The co-culture was exposed in a chamber
attached to a smoking machine which delivered
various amount of mainstream smoke from one, two
or three 3R4F Kentucky reference cigarettes (ISO
smoking conditions). The system was incubated for
24 hours in a cell culture incubator prior to
cytotoxicity and inflammatory cytokines analysis.
Exposure to 1, 2, 3 cigarettes smoke resulted in
about 15%, 50%, 80% cell death, respectively. The
co-culture supernatant was analyzed for a 42-plex
human cytokine panel. Cytokine release was
independent of U937 number in the absence of
smoke, but 8 of 42 cytokines were unique to U937 in
smoke exposed co-culture indicating the role of
U937 cells in smoke response. The levels of most
cytokines were inhibited at 2 or 3 cigarette smoke
exposure due to cytotoxicity. Our in vitro co-culture
study indicates that the presence of macrophage-like
inflammatory cells, U937, is essential to induce
various inflammatory responses typically seen in
animal and human smoking conditions. This coculture system provides an improved, relevant
platform for toxicological inflammatory testing for
cigarette ingredients and prototypes.
P505
PROTECTIVE EFFECT OF SELENIUM AGAINST
CARBOFURAN INDUCED OXIDATIVE STRESS IN RAT
LIVER Hoda M. Nasr*, Fatma El-Demerdash**
*Department of Pest Control and Environmental
Protection, Faculty of Agriculture, Damanhour
University,
Damanhour,
Egypt.
Email:
cohm_hm@yahoo.com,
**
Department
of
Environmental Studies, Institute of Graduate Studies
and Research, Alexandria University, Alexandria,
Egypt. Email: feldemerdash@yahoo.com
Carbofuran (Furadan) is a broad spectrum
carbamate insecticide mainly used to control
household pests. Because of the widespread use of
pesticides for domestic and industrial applications,
evaluation of their toxic effects is of major concern
to public health. Therefore, the present study was
carried out to investigate oxidative stress, lipid
peroxidation and antioxidant enzymes activities
induced by carbofuran in rat liver, and the role of
selenium in alleviating its negative effects. The
administration of carbofuran significantly caused
elevation in LPO level and perturbations in the
activities of antioxidant enzymes including catalase
(CAT), superoxide dismutase (SOD) and glutathione
S-transferase (GST). A significant decrease in
glutathione (GSH) content was observed. Selenium
treatment to carbofuran intoxicated rat decreased
LPO level and normalized CAT, SOD and GST
activities, while GSH content was increased. In
conclusion, Se has beneficial effects and could be
able to antagonize carbofuran toxicity.
P504
DIMETHOATE-INDUCED OXIDATIVE DAMAGE IN
MALE RAT: ATTENUATION BY VITAMIN C Fatma
El-Demerdash, University of Alexandria, Institute of
Graduate Studies and Research, Department of
Environmental Studies, Alexandria, Egypt. Email:
feldemerdash@yahoo.com
The present study is carried out to investigate the
role of vitamin C in protection against oxidative
damage induced by dimethoate insecticide in male
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32ND Annual MEETING
600 series – Data Sets
More than forty marketed drug products
(FDA/EMA dossiers) have been reviewed and
vehicles and excipients used are presented in this
poster. Data includes information on route of
administration, dosage, study duration, and (where
possible) notable reactions. Published literature on
this topic is also included. This provides the nonclinical experimenter with a valuable tool in his or
her work.
P600
(MINI)PIGS
IN
DEVELOPMENTAL
AND
REPRODUCTIVE
TOXICITY
(DART)
STUDIES
Ganderup, NC (1) & Navratil, N (2) 1: Ellegaard
Göttingen Minipigs, Denmark, ncg@minipigs.dk. 2:
Marshall
BioResources,
USA,
nnavratil@marshallbio.com.
Reproductive studies in the context of safety
assessment of new medicines are performed
routinely in a rodent and the rabbit. However, in
cases where the rabbit may not be suitable as the
non-rodent model, the minipig may be a suitable
alternative, and should be considered before
utilising non-human primates (NHPs).
This poster has three components:
4) Male and female reproductive characteristics,
including embryonic development, and a
comparison with other commonly used species.
5) Data about the nature and frequency of
congenital malformations and abnormalities
observed in the Göttingen Minipig production
herd. Although such data cannot be a substitute
for data obtained from control groups, this
information can be valuable when interpreting
DART studies.
6) A literature review on the use of pigs and
minipigs in teratology studies provide additional
knowledge about the species in this context.
Pros and cons of minipigs in the context of DART
studies will also be presented.
Minipigs have been used for regulatory segment II
studies and should be considered as a relevant
alternative to the rabbit (if unsuitable). The minipig
should be considered before using NHPs.
P602
BACKGROUND DATA IN THE INSTRUMENTED AND
NON-INSTRUMENTED
GÖTTINGEN
MINIPIG
Bernier, L., Mansell, P., Copeman, C., Preclinical
Services Charles River Montréal
With recent publications from the European
RETHINK Project on the evaluation of the minipig as
an alternative non-rodent species in toxicity testing,
and following recommendations to systematically
take minipigs into account during selection of an
appropriate species, it is important to evaluate the
background historical data and assess the suitability
of the animal model for various routes of
administration. Minipigs have been used by Charles
River Laboratories as a non-rodent species for
toxicity testing over more than 20 years.
Pharmacokinetic, safety pharmacology, and toxicity
studies using various dose routes including oral
(gavage and pilling), intravenous and subcutaneous
injections or infusion as well as studies utilizing
target tissue dosing; dermal and ocular (instillation,
intravitreal and subretinal injections) administrations
have been conducted in minipigs. Dosing regimens
varied from a single dose to 26-week daily
administration (oral or IV infusion). Data types
collected included clinical observations, body
weights, food consumption, electrocardiograms,
electroretinograms, ophthalmology, ocular pressure,
blood pressure, clinical pathology (hematology,
clinical biochemistry) and anatomic pathology (organ
weights, macroscopic and microscopic findings).
Comparisons of basic parameters obtained from
control minipigs surgically instrumented or surgically
manipulated, with that of minipigs given control
substances orally, revealed that data sets were
generally comparable, with predictable variability
observed in parameters affected by differences in
study design inherent to each route of
administration. In conclusion, models utilizing the
minipig are considered to be predictable and a
suitable alternative as a non-rodent species for use
in toxicology studies.
P601
VEHICLES & EXCIPIENTS UTILISED IN MINIPIGS –
REVIEW OF USE IN MARKETED DRUG PRODUCTS
Ganderup, NC, Ellegaard Göttingen Minipigs, DK.
Selection of suitable vehicles and/or excipients is
critical in both non-clinical and clinical studies as
formulation impacts the intrinsic characteristics of
the final drug product, e.g., (extended) release,
absorption, distribution and (local) tolerance, to
mention some. Inappropriate selection of vehicles
and/or excipients can have negative impact on drug
evaluation (which may be unwarranted) and
consequently delay or stop development. This type
of information is available for mice, rats, rabbits,
dogs and non-human primates (NHP), but
information specific to minipigs is scarce.
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P603
SAFETY ASSESSMENT OF SUBSTANCES IN
ACCORDANCE WITH THE NEW GUIDANCE FOR NEW
DIETARY INGREDIENTS
Gavin P. Thompson and
Gregory J. Sower, ENVIRON International
Corporation, 1702 E. Highland Avenue, Suite 412,
Phoenix, AZ 85016 USA.
In the US, the Dietary Supplement Health and
Education Act of 1994 (DSHEA) established that the
manufacturer or distributor is responsible for
ensuring that its dietary supplements are safe before
they are marketed. Unlike drugs, FDA does not
approve dietary supplements for safety or
effectiveness before they are marketed. However, a
manufacturer or distributor of a new dietary
ingredient (NDI) submits a notification to FDA
containing safety data to support the proposed use
of the NDI. Although FDA does not opine on the
safety of the NDI, it may issue an adverse status
statement declaring the notification contains an
“inadequate basis for reasonable expectation of
safety.” To prevent this, an adequate and
appropriate NDI safety dossier is needed. The
authors investigate how various manufacturing
process changes and various product use scenarios
proposed for the NDI alter the needs of the safety
data set. Strategies for assembling adequate safety
data to support the use of the NDI are discussed. The
authors analyzed the potential impacts of various
processing methods for select ingredients on the
safety of the NDI and its components. While minor
changes in volatile components or concentration in
aqueous solution or a solid in suspension may have
no significant impact on composition and hence
safety, other changes such as hydrolysis or
esterification, removal of some components by
chromatography, distillation or filtration may change
the chemical composition of the NDI. Processing
with a solvent other than water or aqueous ethanol
to make an extract of the NDI may also change the
chemical composition of the ingredient. The impacts
of several alternative processing methods on the
requirements for the safety dossier are considered
and alternative approaches to obtaining adequate
and sufficient data are discussed. The authors
describe a variety of assessment tools including
bridging data from studies of components of the
NDI; and conclude that sufficient data may be
available for an NDI even when the NDI is produced
using new methods or in new formulated products.
P604
SEND: ELECTRONIC SUBMISSION OF NONCLINICAL
DATA
Lou Ann Kramer1, Fred Wood2, Timothy
3
Kropp , Paul Cornwell1, Lorrene A Buckley1, Mary Jo
Brucker4, Christopher Eley5, William Houser6 1 Eli
Lilly & Co., 2 Octagon Research; 3 USFDA; 4 Merck; 5
Pfizer; 6 Bristol Meyer Squibb
Through the collaborative work of contract
research organizations (CROs), industry and FDA, the
production release of the SEND (Standard for
Exchange of Nonclinical Data) Implementation Guide
v 3.0 has been completed (www.cdisc.org/send). A
rapid adoption of this standard is planned, and
regular submissions are expected in 2012.
SEND benefits include increased reviewer
efficiency and enhanced communications between
CROs, sponsors, and FDA’s Center for Drug
Evaluation and Research (CDER). SEND supports
automated creation of tables and graphs and allows
data subsetting and mining, thus facilitating
collaborative inter-industry efforts to interrogate
information across boundaries. SEND will also
enable FDA’s objective to develop a reposit-ory for
all study data, clinical and nonclinical. SEND datasets
are intended to replace data tabulations currently
submitted as paper or PDFs; the study report will
continue to provide methods and interpretive
information.
The purpose of SEND is to promote improvements
in submission efficiency and quality through the
establishment of a single international data standard
for nonclinical data. Development of this standard
began more than a decade ago and has gained
momentum through piloting programs and the
active participation of more than 50 volunteers
across a wide array of pharmaceutical companies,
CROs, vendors and the FDA. The current release
defines standards for general toxicology, and
carcinogenicity studies. Work is continuing to
finalize standards for safety pharmacology and
reproductive toxicology studies. CDER has already
established processes and technology infrastructure
to support the receipt, processing, review, and
archiving of SEND formatted datasets.
This abstract reflects the views of the author and
should not be construed to represent FDA’s views or
policies
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32ND Annual MEETING
P605
ANTICANER DRUG-INDUCED CARDIOTOXICITY:: A
RETROSPECTIVE ANALYSIS OF THE ACCURACY OF
NONCLINICAL SAFETY STUDIES TO PREDICT FOR
ADVERSE CARDIOVASCULAR EVENTS IN THE CLINIC
Craig D. Fisher, Peter F. Smith and Vivek J. Kadambi
Drug-induced cardiovascular toxicity can manifest
as changes in blood pressure, arrhythmias (especially
torsades de pointes induced by QT prolonging
drugs), myocardial ischemia, thrombosis or
impairment in myocardial contraction and/or
relaxation. In the clinic, these toxicities can range
from subclinical abnormalities to life-threatening
and in some cases fatal events. Anticancer drugs
have long been known to cause adverse
cardiovascular events in the clinic.
However,
because these drugs are highly effective in settings
where treatment options are limited, cardiovascular
risk is rarely a development limiting barrier. The
prevalence of literature highlighting anticancer druginduced cardiovascular toxicity prompted us to
conduct a meta-analysis to determine whether
nonclinical safety data submitted for approval of
these drugs accurately predicted for adverse
cardiovascular events observed in the clinic.
Inclusion criteria consisted of anticancer drugs with
(1) cardiovascular toxicity listed as a “boxed
warning” or “adverse event” on the drug label, and
(2) accessible FDA or EMA drug approval package
documents. Our results revealed that of the 33
anticancer drugs analyzed, approved between 1993
and 2011, only 17 had definitive findings of
cardiovascular toxicity identified in nonclinical safety
studies. Moreover, 2 drugs with boxed warnings for
cardiovascular toxicity (trastuzumab and arsenic
trioxide) had no indication of cardiac abnormalities
in their nonclinical safety studies. Although results
of this analysis suggest that traditional nonclinical
safety studies may not accurately predict for
anticancer drug-induced cardiotoxicity in the clinic, it
should be noted that cancer patients represent a
population with comorbidities and/or a history of
prior treatment that may predispose them to
adverse cardiotoxic events upon further drug
administration. Taking this into account, the authors
conclude that the addition of specialized nonclinical
studies, including the use of stem cell derived
cardiomyocytes as well as animal models with preexisting disease or pre-exposure to relevant drugs
(e.g. anthracyclines), may be useful when assessing
the risk of anticancer drugs for cardiotoxicity in this
complicated patient population.
P606
AN INTEGRATED PREDICTION SYSTEM TO SUPPORT
TOXICOLOGY ASSESSMENTS OF CHEMICALS.
Bower D1, Cross KP1, Crump M1, Miller S1, Myatt GJ1,
Saiahkov R3, Tice RR2, Wright M4 1) Leadscope, Inc.,
Columbus, OH USA. 2) National Institute for
Environmental Health Sciences, RTP, NC USA. 3)
MultiCASE, Inc., Beachwood, OH USA. 4) Lhasa
Limited, Leeds, UK
Accessing toxicology data is challenging today
because the data is located in many different places,
with each database requiring the use of separate
applications or web sites to search the information.
Supplementing known information with results from
multiple types of predictive models is often
desirable; however, it can be difficult to use different
software applications. This poster describes a
prototype of an integrated prediction system that
brings together toxicity data and predictions within a
single graphical user interface running in a web
browser. This user interface provides access to
toxicology endpoints and studies from multiple
databases, including public and proprietary data. The
user is able to assess the toxicity of an existing or
new compound using QSAR models or structural
alerts from multiple suppliers including Leadscope,
Inc., Lhasa Limited, and MultiCASE, Inc. The system
was designed for use by scientists with different
backgrounds; hence, it had to be easy to use and
transparent to all stake holders. This poster will
illustrate how the platform can be used to profile a
set of compounds based on known toxicity
information, browse prediction model results and
explanations from multiple vendors and understand
associations between different toxicity tests.
P607
IN
VIVO
COMPARABILITY
STUDIES
FOR
MONOCLONAL
ANTIBODY
PRODUCTS:
A
REGULATORY INTELLIGENCE REVIEW.
Elena
Whitley1 and John An2. 1Preclinical Development
and 2Global Regulatory Intelligence, Global
Regulatory Affairs, PPD, Inc.
Regulatory guidances state that comparability
assessment of biotechnology-derived products is
required to assess the potential impact of
manufacturing changes on quality, safety and
efficacy. Nonclinical comparability programs are
generally designed in a step-wise fashion.
Physicochemical and biochemical analytical data and
results of in vitro pharmacology assays inform
decisions on whether or not in vivo nonclinical
studies are warranted, and if so, how they should be
designed. Regulatory guidances on monoclonal
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
antibody development and comparability testing are
largely silent on specific nonclinical study design
features.
A regulatory intelligence review of publicly
available
information
was
performed
for
26 monoclonal antibody products approved from
1994 to 2011, with a focus on nonclinical in vitro and
in vivo comparability programs as described in
regulatory authority approval packages. When
nonclinical studies were presented, comparative in
vitro pharmacology studies and single-dose
pharmacokinetic/pharmacodynamic (PK/PD) studies
were more common than repeat-dose toxicity
studies, consistent with an incremental approach to
comparability assessment. The implications of the
results of the regulatory intelligence review for
nonclinical development of innovator and biosimilar
monoclonal antibody products are discussed.
Among the data analyzed, the incidence of
spontaneously
occurring
nonneoplastic
and
neoplastic histologic lesions was determined and are
presented in this work.
Lesions included
spontaneous degenerative and inflammatory
changes, as well as a limited number of neoplasms.
Additionally, histopathologic findings considered
part of normal morphologic changes due to age
progression are also discussed. Overall, the purpose
of this data is to facilitate the selection of the most
appropriate animal model for subchronic toxicity
studies and to facilitate the interpretation of results
using the Harlan RccHan:Wistar rat strain.
P609
A BATTERY OF ASSAYS FOR SELECTION OF DERMAL
DRUG CANDIDATES - AND THE REGULATORY NONCLINICAL SAFETY PROGRAM FOR DERMAL DRUGS
Jens Thing Mortensen, CiToxLAB Scantox, Denmark
and David J Esdaile, CiToxLAB Hungary
Screening of molecules as candidates in a new
dermal drug program is mostly based on the desired
pharmacological properties and potency of the
molecules (e.g. anti-inflammatory, anti-proliferative,
anti-microbial, etc.) and their “drugability” (chemical
structure, solubility, etc. that lead to desirable ADME
properties). However, once the screening procedure
has reduced the number of dermal candidate
molecules to a relatively small number, it is
important to assess these molecules for potential
adverse effects. For dermal drug candidates, which
will reach a high concentration in the skin, local skin
irritation, contact sensitization and phototoxicity,
are important hazards that should be assessed
before making the final selection. The skin
penetration properties of these molecules, or the
influence of various formulation ingredients on the
penetration of the molecule into the skin are
important. We propose a tiered battery of in silico, in
vitro and in vivo assays focused on providing a range
of data to assist the development program in
candidate selection for active ingredients and
formulations.
Once the final, optimised dermal drug candidate
has been selected, a regulatory non-clinical safety
program must be conducted to support clinical trial
and marketing of the drug. The program will comply
with regulatory guidance and be built in a step-wise
manner to support each consecutive phase of the
specific dermal clinical trial program. Important
program and study design decisions to be made
include: 1) choice of rodent and non-rodent species
for the program, 2) choice of a suitable dermal
vehicle for the non-clinical dermal studies, and 3)
P608
INCIDENCE OF NONNEOPLASTIC AND NEOPLASTIC
LESIONS IN HISTORICAL CONTROL HARLAN
RCC:HAN WISTAR RATS AFTER 28, 90, AND 180
DAYS OF ORAL GAVAGE DOSING
Hollie Skaggs,
PhD1, Rachel Avery, BS1, and Brad Blankenship, DVM,
Diplomate, ACVP1
Covance Laboratories, Inc.,
Madison, WI
Historical control data are important for the
evaluation of certain histologic lesions identified
during subchronic rodent toxicity studies. For
uncommon lesions or lesions of uncertain
relationship to the test article, historical control data
can provide information about the incidence of
spontaneously occurring background lesions in the
species and strain of animal used on test. By
providing this information, historical control data
help support the significance (or lack thereof) of
common and uncommon histopathology findings. In
this work, an initial study was performed to
investigate and develop a preliminary historical
control database for the Harlan Rcc:Han Wistar rat
strain at Covance Laboratories, Madison. Sixty male
and sixty female Harlan RccHan:Wistar rats were
sacrificed after 28, 90, or 180 days (360 animals
total) of daily oral gavage dosing with reverse
osmosis water. At initiation, animals were 4 to 8
weeks of age. Clinical signs, body weight, and food
consumption were recorded; and hematology,
clinical chemistry, coagulation, and urinalysis
samples were analyzed. Animals were necropsied;
macroscopic
observations
recorded;
organs
weighed; and tissues processed for microscopic
evaluation. Electron microscopy was performed on
selected tissues from a limited number of animals.
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AMERICAN COLLEGE OF TOXICOLOGY
potential inclusion of systemic
administration in the tox program.
route
32ND Annual MEETING
of
2011
P701
NONCLINICAL TOXICITY STUDIES FOR A NOVEL
ANTICANCER AGENT, LOR-253
Yoon Lee1, Mario
1
2
Huesca , Geoff Goodfellow , Jon Daniels2, Aiping
Young1 1 Lorus Therapeutics Inc.; 2 Intrinsik Health
Sciences Inc.
LOR-253 is a first-in-class inhibitor of the Metal
Transcription Factor-1 (MTF-1) with a novel mode of
action. This consists of the induction of the tumor
suppressor factor Krüppel like factor 4 (KLF4) leading
to the down regulation of cyclin D1, an important
regulator of cell cycle progression and cell
proliferation, and decreased expression of genes
involved in tumor hypoxia and angiogenesis. The
toxicity profile of LOR-253 HCl has been investigated
in intravenous (IV) infusion toxicology studies in
Sprague-Dawley rats and Beagle dogs. In the singledose toxicity studies, LOR-253 HCl was administered
by IV infusion (over 4 hours) to rats at doses up to
384 mg/m2 and to dogs at doses up to 840 mg/m2.
In rats, LOR-253 HCl was well tolerated at all dose
levels tested and was not associated with any
adverse effects or histopathological findings. In
dogs, LOR-253 HCl was well tolerated up to
350 mg/m2, with the maximum tolerated dose
(MTD) determined to be 840 mg/m2, based on
changes in body weight, clinical chemistry
parameters and kidney microscopic findings. In the
pivotal GLP, 4-cycle toxicity studies in rats
(0/125/200/350 mg/m2) and dogs (0/175/250/350
mg/m2), a single cycle was equivalent to 5
consecutive days of dosing per week. Based on the
results of these studies, the kidney, liver/biliary
gland, and blood were identified as primary target
organs of toxicity for LOR-253 HCl. Toxicokinetic
results showed significant dose-related exposure.
The results of the pivotal LOR-253 HCl toxicity
studies in rats (STD10 >200 mg/m2) and dogs
(HNSTD= 250 mg/m2) supported the initiation of a
Phase 1 clinical trial in cancer patients at a starting
dose of 20 mg/m2 (1/10 of the STD10). In the Phase
1 trial, the dose frequency was reduced to a 2-day
dosing period over 14 days based on supporting data
from mouse xenograft studies.
700 series – Preclinical Safety
Assessment
P700
THE PRECLINICAL SAFETY ASSESSMENT OF
LY2196044, A PAN OPIOID ANTAGONIST FOR THE
TREATMENT OF ALCOHOL USE DISORDERS
WJ
Breslin, PJ Cocke. Lilly Research Laboratories,
Indianapolis, IN 46285.
LY2196044, a pan (kappa, mu and delta) opioid
receptor antagonist under development for the
treatment of alcohol use disorders was evaluated in
a series of nonclinical acute, repeat-dose,
reproductive and genetic toxicology and safety
pharmacology studies. A single oral dose of 2000
mg/kg given to rats resulted in no important effects.
Repeated oral doses of 1500 mg/kg to rats and dogs
produced dose-limiting toxicity indicative of
excitatory central nervous system (CNS) toxicity,
including
convulsions
and
increased
mortality/euthanasia. In a rat 6-month study, males
given
1500
mg/kg/day
also
exhibited
atrophy/degeneration of the testes and histiocytosis
in the ileum and mesenteric lymph node. These
changes occurred at exposure levels ≥28x the
exposure at the maximum proposed clinical dose of
250 mg and were completely (testes) or partially
(ileum and lymph node) reversible following a 1month recovery period. No clear adverse effects
were observed in a 9-month dog study at doses up
to 1000 mg/kg. LY2196044 was negative in a
standard battery of genotoxicity tests and no
adverse reproductive or developmental effects were
observed at doses up to 1000 mg/kg in rats or 500
mg/kg in rabbits.
In a mouse CNS safety
pharmacology study, transient hypoactivity and
enhanced effects of barbiturates were observed at
300 mg/kg.
No substantive changes in
cardiovascular function or QTc interval were
observed in dogs at doses up to 800 mg/kg and no
changes in respiratory function in rats or
gastrointestinal motility in mice were observed at
doses up to 300 mg/kg. In conclusion, the results of
nonclinical toxicology and safety pharmacology
studies demonstrate an acceptable safety profile for
the clinical study of LY2196044. The lowest margins
of safety (MOS) for LY2196044 based on systemic
exposure from chronic rat and dog studies and the
highest proposed clinical dose of 250 mg were 5-fold
for Cmax (rats) and 6-fold for AUC (dog).
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2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
P702
NONCLINICAL SAFETY EVALUATION OF AN
ANTIBODY-DRUG CONJUGATE (STEAP1 ADC) FOR
THE POTENTIAL TREATMENT OF PROSTATE
CANCER.
Willy A. Solis, Bonnee Rubinfeld, Kedan
Lin, Douglas Leipold, Michael Mamounas, Khiem
Tran, Fiona Zhong, Joseph Beyer, Kelly M. Flagella,
Reina N. Fuji, Genentech, South San Francisco,
California.
Antibody-drug conjugates (ADCs) constitute an
expanding class of therapeutic molecules in
preclinical and clinical development for oncology
indications. These biologic-based drugs are designed
to increase delivery of cytotoxic payloads to tumor
targets in order to improve efficacy and minimize
toxicity. Six-transmembrane epithelial antigen of the
prostate-1 (STEAP1) is a multi-transmembrane, cellsurface antigen that is over expressed in the majority
of human epithelial prostate cancers. STEAP1 ADC is
comprised of anti-STEAP1 monoclonal antibody and
monomethyl auristatin E (MMAE). MMAE is a
potent anti-mitotic agent that is conjugated to the
antibody through an enzyme-cleavable linker.
STEAP1 ADC has anti-tumor activity in STEAP1positive explant and xenograft prostate cancer
models. The safety profile of STEAP1 ADC was
evaluated in antigen-dependent and antigenindependent animal models. The main clinical and
anatomic pathology findings showed toxicities to the
bone marrow, liver, and testis. These findings were
considered
antigen-independent,
clinically
manageable, and consistent with the antiproliferative effects of MMAE. In summary, STEAP1
ADC shows favorable efficacy and safety profiles in
nonclinical models and is currently being evaluated
as a new therapy for prostate cancer patients.
(enzyme IC50 of 7 nM) and slightly less potency for
the Janus kinase-2 (Jak2; enzyme IC50 of 30 nM) and
colony stimulating factor-1 receptor (CSF1-R;
enzyme IC50 of 28 nM) targets. The objective of this
study was to determine the effects of CC-118 in
Sprague-Dawley rats when dosed once daily via oral
gavage for 7 days. In female rats dosed with 0, 50,
200, 400, and 1000 mg/kg/day, doses of 400 and
1000 mg/kg/day were not tolerated with deaths
and/or early sacrifice required by Days 3 – 6. Doses
of 0, 25, 50, and 200 mg/kg/day were well-tolerated
in male rats. Accumulation of CC-118 was observed
at doses greater than 200 mg/kg/day, resulting in
both higher Cmax and AUC levels upon repeated
dosing. Exposures were generally similar across
doses between males and females. In both sexes,
decreased body weight was observed at ≥200
mg/kg/day and relative spleen and thymus weights
were decreased at ≥200 mg/kg/day. Hematological
changes included increased neutrophil counts at
≥200 mg/kg/day and decreased white blood cell,
lymphocyte, and eosinophil counts at 400
mg/kg/day. Increased serum blood urea nitrogen
was observed at ≥200 mg/kg/day and serum alanine
transaminase and aspartate transaminase were
observed at ≥200 mg/kg/day. At necropsy, the
thymus and spleen were small and the mesenteric
lymph nodes were mottled red.
Microscopic
changes consisted of myelosuppression (bone
marrow hypocellularity)
and lymph node
erythrocytosis at ≥50 mg/kg/day and lymphoid
depletion (thymus and spleen) and femur physeal
dysplasia in females only at ≥200 mg/kg/day. These
changes were generally attributed to inhibition of
targeted kinases including Syk (lymphoid depletion),
Jak2 (myelosuppression), and CSF1-R (physeal
dysplasia, splenic red pulp atrophy, and elevated
liver enzymes).
800 series – Molecular Mechanisms
P801
TOXICOLOGY PROFILE OF SMALL MOLECULE IAP
ANTAGONIST GDC-0152 IS ASSOCIATED WITH TNFALPHA PHARMACOLOGY
Rebecca Erickson12,
12
Jacqueline Tarrant , Gary Cain12, Noel Dybdal12,
Sock-Cheng Lewin-Koh13, Harvey Wong14, Elizabeth
Blackwood15, Kristina West15, Davi Almeida12, Kenjie
Amemiya12, Donna Dambach12, Wayne Fairbrother16,
Dolo Diaz12 1 Genentech, South San Francisco, CA, 2
Dept. of Safety Assessment. 3 Dept. of Nonclinical
Biostatistics, 4 Dept. of Drug Metabolism and
Pharmacokinetics, 5 Dept. of Translational Oncology,
6
Dept. of Early Stage Discovery Biochemistry.
Inhibitor of apoptosis (IAP) proteins suppress
apoptosis and are overexpressed in a variety of
P800
TOXICOLOGICAL ASSESSMENT OF A SPLEEN
TYROSINE KINASE INHIBITOR, CC-118, IN SPRAGUEDAWLEY RATS. Dinah L. Misner, Mike A. Breider,
Kamran Ghoreishi, Brandon Jeffy, Dale Baker, and
Rosana Magpantay. Exploratory Toxicology, Celgene
Corporation, San Diego, CA.
Inhibition of the spleen tyrosine kinase (Syk)
enzyme has been advocated as therapy for
autoimmune disease, due to the important role of
Syk in signaling downstream from immunoglobulin
receptors on cells integral to the inflammatory
process. CC-118 is a small molecule selective kinase
inhibitor with high potency against the Syk target
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
cancers. GDC-0152 is a small molecule that triggers
tumor cell apoptosis by selectively antagonizing
IAPs. Several cytokines and chemokines are
expressed in tumor cells as a result of GDC-0152induced NFκB transcriptional activity, with tumor
necrosis factor alpha (TNFα) being the most
important for single-agent tumor activity. However,
a variety of normal cells also produce TNFα upon IAP
antagonism, which may contribute to both efficacy
and toxicity. Here, we characterized the toxicology
profile of GDC-0152 in rats and dogs following
intravenous dose administration once every two
weeks. Findings in both species consisted of a doserelated, acute inflammatory response and hepatic
injury. Specifically, in-life observations included
cytokine/chemokine production, an inflammatory
leukogram, and elevated transaminases in addition
to histopathological findings of inflammatory
infiltrates and apoptosis/necrosis in multiple
tissues. All findings were biologically linked, by
direct or indirect mechanisms, to TNFα and are
therefore expected to track with efficacy. The
relationships between plasma cytokine/chemokine
levels, specific pathology findings, and GDC0152 plasma exposures were explored. Elevations in
blood neutrophil count, serum MCP-1 and other
markers of inflammation corresponded to GDC-0152
exposure
and
toxicity and
show
promise
for further safety biomarker qualification.
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32ND Annual MEETING
2011
ABSTRACT AUTHORS
Adams, T.B. – XV
Adeyemi, O.S. – P105
Albretsen, J. – P307
Alden, C.L. – P200
Almeida, D. - P801
Amemiya, K. – P801
An, J. – P607
Arevalo, M. – P213
Arocena, M. – P114
Arvidson, K.B. – XV
Atta-Safoh, S. – P213
Avalos, J. – P102
Avery, R. – P608
Bagley, J. – P212
Bailey, D. – P304
Baird, T. – XII, P401
Baker, D. – P800
Balali-Mood, M. – P501
Barlow, N. – VIII
Beck, M.J. – P407, P408,
P409
Beck, S. – IX
Beck, T. – P209
Beierschmitt, W.P. – IX
Belote, D. – P307
Bennett, M.R. – P407
Benz, R.D. – VII
Berman, C.L. – X
Bernier, L. – P602
Beyer, J. – P702
Bhattacharya, A. – P201
Bialecki, R. – XVII
Bijl, S. – P412
Blackwood, E. – P801
Blair, E. – P203
Blankenship, B. 0 P608
Blumer, K. – XVII
Bogie, H. – P215
Boogaard, P.J. – XIII
Bouchard, G. F. – P111, P203,
P216
Bourgeois, A.L. – P305
Boverhof, D. – P108
Bower, D. – P606
Bowes, J. – P117
Brahmankar, M. – P108
Breider, M.A. – P800
Brennan, M. – P114
Breslin, W.J. – P700
Breuning-Wright, A. – P116
Brown, A.M. – P114, P116
Brown, L. – P111, P203, P216
Brown, R. – P304
Bruce, S. – P213
Brucker, M.J. – P604
Buckley, L.A. – P604
Bunch, R.T. – P414
Burch, C.R. – P404
Burks, Z. – P203
Cagle, C.B. – P405
Cain, G. – P801
Cao, L. – P410
Carathers, M.R. – P104, P105
Cardoza, K. – P200
Caron, S. – P303
Carraway, J.W. – I
Carter, C.A. – P502
Cerven, D.R. – P102, P104,
P105, P106
Chaves, A. – P202
Chen, H. – P214
Chesnut-Speelman, J. – P117
Ciaravino, L. – P100
Clark, C.R. – XIII
Clawson, C. – P404
Cocke, P.J. – P700
Coffey, C. – P110
Contrera, J.F. – P119
Copeman, C. – P303, P602
Cornwell, P. – P604
Coston, T. – P406
Cracknell, A. – P207
Crawford, J. – P204
Cross, K.P. – XV, P119, P606
Crump, M. – P606
112
Csizmadia, V. – P200
Cunningham, M.J. – P103
Cuppen, E. – P204
D’Andrea, A. – P410
Dadpour, B. – P501
Dailey, T. – P100
Dalal, V. – P108
Dambach, D. – P801
Damen, J. – P400
Daniels, J. – P701
Davies, M.H. – P414
de Kimpe, S.J. – P411, P412,
P413
Debelie, F. – P213
deBruin, A. – P204
DeGeorge, G.L. – P102, P103,
P104, P105, P106
DeGraw, T. – P101
Der, K. – P410
Dertinger, S. – P213
Desai, P. – P118
Desmond, D.J. – P115
Dhar, P. – P201
Diaz, D. – P801
Diekmann, H. – P207, P208
DiNovi, M.J. – XV
Dixit, R. – P302
Dodd, A. – P207
Donahue, D.A. – P102
Donegan, M. – P414
Dooley, J. – IV
Dorsam, R.T. –X
Dubach, J. – P210
Dubey, V. – P108
Dybdal, N. – P801
Eaves, A. – P400
El Karadawey, M.H. – P300
El-Demerdash, F. – P504,
P505
Elden, M.fa – P300
Eley, C. – P604
Ellis, A. – XIV
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
Erickson, R. – P801
Esdaile, D.J. – P609
Evans, T. – P216
Grompe, M. – V
Gudelsky, G. – P118
Guenther, C. – P406
Jordan, H. – P304
Jortner, B. – P200
Faiola, B. – P304
Fairbrother, W. – P801
Faqi, A.S. – P401
Fareed, J. – P210
Farzim, C. – P400
Fedyk, E.R. – P200
Feilden, A. – IX
Felter, S.P. – XV
Ferrari, N. – X
Fisher, C.D. – P605
Flagella, K.M. – P702
Flint, O. – VII
Flueckiger, A. – P113
Forbes, D. – P406
Ford, Jr., J. – P307
Foster, A.F. – P117
Franklin, P. – P209
Frantz, S. – P110
Freeman, J.J. – XIII
Friedrichs, G. – P202, P205
Fryer, R. – P402
Fuji, R.N. – P702
Hackman, M.L. – P408
Hadd, S. – P110
Hailey, J. – P304
Hall, D. – P102
Hall, L. – P212
Hamlin, R. – XII
Handler, J.A. – I
Hanks, B.C. – P203
Hanks, C. – P111
Hargreaves, D. – P110
Harrison, P. – P402
Harrison, T. – P410
Harrouk, W.A. – XIV
Hasselgren, C. – VII
Hastings, K.L. - XVIII
Heidel, S.M. – XVIII
Henry, S. – X
Hermsen, R. – P204
Higgins, D. – P206
Hill, A. – P207, P208
Hoagland, K. – P202
Hoberman, A. – P114
Hobson, D.W. – I
Holzgrefe, H. – XVII
Hoppensteadt, D.A. – P210
Hopper, D. – P101
Horlen, K.P. – P111, P203
Horn, K. – XVI
Houser, W. – P604
Howard, K. – V
Huber, M. – P400
Hudak, A. – P402
Huesca, M. – P701
Hummer, T. – IV
Kadambi, V.J. – P200, P605
Kallman, M.J. – XVI
Katavolos, P. – P115
Kelley, T. – P213
Kemp, D. – P304
Kenna, J.G. – P117
Kenney, J. – P107
Kianoush, S. – P501
Kimbrough, C. – P107
Kinney, J.C. – P115
Klug-LaForce, M. – P213
Kolbeck, R. – P302
Kolfschoten, I.G.M. – P412
Kornbrust, D. – X
Kosco, J. – P307
Kramer, J.K. – P116
Kramer, L.A. – P604
Kreet, M.H. – P300
Krishnan, M. – P118
Kropp, T. – P604
Krsmanovic, B. – P213
Krueger, J. – VIII
Kuiper, R.V. – P204
Gad, S.C. – I
Galijatovic-Idrizbegovic, A. –
V
Gallacher, M. - P200
Gallenberg, L.A. – P115
Ganderup, N.C. – P403, P600
Gao, Y-J. – P205
Garside, H.J. – P117
Genter, M.B. – P118
Gerenser, P. – P202
Germann, P-G. – III
Ghoreishi, K. – P800
Gien, B. – P101
Gilbert, K.S. – P405
Gizzi, J. – P215
Godin, C.S. – P305, P306
Goodfellow, G. – P701
Grady-Styring, T. – P202
Green, C. – P410
Greene, N. – VII
Iciek, L. – IX
Ivens, I.A. – P308
James, N. – P100
Jamison, J. – VI
Jeffy, B. – P800
Johanssen, S. - P406
Jones, M. – P207, P208
113
Lainee, P. – XII
Lalayeva, N. – P209
Lane, R. – P101
Lange, R.W. – P414
Lau, E. – P400
Lawlor, T. – P214
Learn, D. – P114, P406
Lee, D. – XI
Lee, K. – IV
Lee, P. – II
Lee, Y. – P701
Leininger, J.R. – P302
Leipold, D. – P702
Leishman, D.J. – P404
Lewin-Koh, S-C. – P801
Lin, K. – P702
Lincoln, K. – P402
Liu, J. – P111, P203
AMERICAN COLLEGE OF TOXICOLOGY
Ma, J. – P410
Maciel, M. – P305, P306
Magpantay, R. – P800
Main, B.W. – P404
Makori, N. – P209
Maltas, J. – P101
Mamounas, M. – P702
Manetz, T.S. – P302
Manish, R. – P108
Mann, P.C. – III
Mansell, P. – P602
Marcoe, K.F. – P117
Maronpot, R.R. – P502
Matthews, E. – XV
Mattis, C.R. – P115
McDonald, T.A. – P308
McDorman, K.S. – III
McGeehan, E. – P210
McGraw, J. – P211
McInally, K. – P215
McKee, R.H. – XIII
McKeon, M. – P214
Mehra, R.D. – P201
Merrill, C. – P304
Meyer, K. – P410
Miller, S. – P606
Mineo, A. – P402
Mirsalis, J. – P410
Misner, D.L. – P800
Misra, M – P502, P503
Mistry, B. – P101
Miyamoto, M. – P206
Monteith, D. – P400
Moore, C. – P203, P307
Moose, T. – P107
Moradi, V. – P501
Morissette, P. – P202
Mortensen, J.T. – P609
Mounho, B.J. – XVIII
Mousavi, S.R. – P501
Mullin, M. – P107
Murli, H. – P214
Murphy, O. – P207
Murphy, V.A. – II
Murray, J. – XI
Muthukumarana, A. – P402
Myatt, G.J. – P116, P606
32ND Annual MEETING
Mylchreest, E. – P405
Nagata, R. – P209
Nasr, H.M. – P505
Navratil, N. – P403
Nemec, M.D. – P407, P408,
P409
Ng, H. – P410
Nicolich. M. – XIII
Niehoff, M. – XII
Nishida, M. – P202
Nodop Mazurek, S. – P402
O’Day, C. – P117
O’Dowd, A. – P305, P306
Obejero-Paz, C. – P116
Oneda, S. – P209
Ontano, E. – P212
Ovechkina, Y. – P117
Pack, F. – P402
Palmby, T. – II
Pandey, S. – P108
Paranjpel, M. – P213
Parman, T. – P410
Patel, R. – P108
Perrone, R.K. – P414
Pershing, M.L. – P409
Pfister, T. – P112
Phagura, A. – P212
Phillipa, J. – P402
Piehl, M. – P106
Plumb, A. – P101
Polk, W. – P503
Ponstein-Simarro Doorten, Y.
– P411, P412, P413
Poole, S. – P305
Poulin, D. – P215
Powley, M.W. – V, VII
Pratt, L.F. – P103
Prefontaine, A. – P303
Pula, K. – P205
Pyrah, I. – II
Reid, L. – XIV
Render, J.A. – VI
Renna, S. – P203
114
2011
Resendez, J.C. – P401
Reynolds, V.L. – P404
Ricci, M.S. – XI
Richardson, M. – P208
Riley, P. – P204
Risvanis, J. – P109
Rivera, M.I. – VI
Roberts, D.J. – P214
Rocha, B. – XVI
Rodriguez, R. – P212
Rohr, A. – P100
Rubinfeld, B. – P702
Ruppert, G. – P110
Ryan, P.R. – P302
Sadeghi, M. – P501
Saiahkov, R. – P606
Salata, J. – P202
Salcedo, T.W. – P414
Sambuco, C. – P406
Sanders, M. – P113
Sanderson, T.P. – P414
Sareen, P. – P213
Sauer, J-M. – P307
Savarino, S. – P305, P306
Scheer, N. – V
Schoenborn, T. – P100
Scholzen, S. – P211
Schuette, D. – P307
Schwartz, M. – P114
Sentz, J. – P206
Sheehan, J. – P206
Sheevers, H.V. – II
Shelton, M. – I
Shi, J. – P213
Shimizu, B. – P410
Silverman, L. – P200
Siple, J. – P107
Skaggs, H. – P608
Sly, J. – P213
Smith, J. – P402
Smith, P.F. – P605
Sokolowska, M. – XVI
Solis, W.A. – P702
Sower, G.J. – P603
Spooner, N. – P107
Springer, S. – P213
AMERICAN COLLEGE OF TOXICOLOGY
Stankowski, Jr., L.F. – P213,
P214
Steve, D. – P202
Stokes, A. – P107
Stout, R. – P110
Stump, D.G. – P407, P408,
P409
Sulaiman, F.A. – P105
Szabol, K. – P213
Tam, A. – P400
Tao, J. – P104
Tarrant, J. – P801
Tedesco, R. – P205
Thakur, A. – P214
Thompson, G.P. – P603
Tice, R.R. – P606
Tiwari, V.K. – P108
Todd, M. – XI
Toonen, P.W. – P204
Toot, J.D. – P407, P408, P409
Topper, M. – XVIII
Torti, V. – VI
Tran, K. – P702
32ND Annual MEETING
Trask, Jr., O.J. – VIII
Travis, J. – P202
Trickey, J. – P216
Trudel, Y. – P303
Turner, P.V. – XVII
Valerio, L.G. – XV
Van Boxtel, R. – P204
Van Heesch, S. – P204
Van Steenhouse, J. – P100
Vana, L.M. – P407
Velasco, M. – P500
Verma, R. – P108
2011
Wenzel, H. – P305
West, K. – P801
White, D. – P203
White, P. – P101
Whitley, E. – P607
Whittaker, D. – P109
Wilker, C. – XIV
Woltmann, R. – P202
Wong, H. – P801
Wood, F. – P604
Woolhiser, M. – P108
Wright, M. – P606
Xu, Y. – P214
Waites, R. – P113
Walgren, J.L. – XVI
Waller, D. – P210, P211
Wallis, R. – XII
Wang, B. – P302
Warren, E. – P100
Warrior, U. – P117
Watson, R. – P209
Weber, K. – III
Webster, L. – P109
115
Yeager, R.L. – P115
Young, A. – P701
Young, G.D. – VIII
Zhong, F. – P702
Zhou, Y-Y. – P202, P205
Zingaro, G. – P202
Zuwannin, L. – P307
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
THANK YOU TO OUR EXHIBITORS
Advion BioServices
Ithaca NY
www.advion.com
Cerep Inc.
Redmond, WA
www.cerep.com
AVANZA Laboratories, LLC
Gaithersburg, MD
www.avanzalaboratories.com
ChanTest Corporation
Cleveland, OH
www.chantest.com
BASi (Bioanalyticl Systems)
West Lafayette, IN
www.basinc.com
Charles River
Wilmington, MA
www.criver.com
Battelle
Columbus, OH
www.battelle.org
CiToxLab
Laval, Canada
www.citoxlab.com
BioReliance Corporation
Rockville, MD
www.bioreliance.com
CorDynamics, Inc.
Chicago, IL
www.cordynamics.com
BioTox Sciences
San Diego, CA
www.biotoxsciences.com
Covance Laboratories, Inc.
Madison WI
www.covance.com
Calvert Laboratories
Scott Township, PA
www.calvertlabs.com
CRC Press/Taylor & Francis
Group LLC
Boca Raton, FL
www.crcpress.com
HistoTox Labs., Inc.
Boulder, CO
www.histotoxlabs.com
Data Sciences International
St. Paul, MN
www.datasci.com
HSRL, Inc.
Mount Jackson, VA
www.hsrl.org
CeeTox, Inc.
Kalamazoo, MI
www.ceetox.com
116
emka TECHNOLOGIES
Falls Church, VA
www.emkatech.com
EPL, Inc.
Sterling, VA
www.epl-inc.com
Evotec (UK) Limited
Abingdon, United Kingdom
www.evotec.com
Experimur
Chicago IL
www.experimur.com
Frontier BioSciences, Inc.
Germantown, MD
www.frontierbsi.com
Harlan Laboratories, Inc.
Indianapolis, IN
www.harlan.com
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
Huntingdon Life Sciences
East Millstone, NJ
www.huntingdon.com
Pacific BioLabs
Hercules, CA
www.pacificbiolabs.com
SAGE
Thousand Oaks, CA
www.sagepub.com
IIT Research Institute (IITRI)
Chicago, IL
www.iitri.org
PDS Preclinical Data Systems,
Inc.
Mt. Arlington, NJ
www.pds-america.com
SAI Infusion Technologies
(Strategic Applications, Inc.)
Libertyville, IL
www.sai-infusion.com
Pharmaron Inc.
Louisville, KY
www.pharmaron.com
Seventh Wave Laboratories
LLC
Chesterfield, MO
www.7thwavelabs.com
ITR Laboratories Canada Inc.
Baie d’Urfe, Canada
www.itrlab.com
Leadscope, Inc.
Columbus, OH
www.leadscope.com
Lovelace Respiratory
Research Institute
Albuquerque, NM
www.lrri.org
Marshall BioResources
North Rose, NY
www.marshallbio.com
MetaSystems
Waltham, MA
www.metasystems.org
Millar Instruments, Inc.
Houston TX
www.millar.com
MPI Research
Mattawan, MI
www.mpiresearch.com
Pre-clinical Research Services,
Inc.
Fort Collins, CO
www.preclinicalresearch.com
PreLabs
Oak Park, IL
www.prelabs.com
Primate Products, Inc.
Immokalee, FL
www.primateproducts.com
Product Safety Labs
Dayton, NJ
www.productsafetylabs.com
QPS
Newark, DE
www.qps.com
Ricerca Biosciences
Concord, OH
www.ricerca.com
117
Sinclair Bio Resources
Columbia, MO
www.sinclairbioresources.
com
Sinclair Research Center
Auxvasse, MO
www.sinclairreserch.com
SNBL USA, Ltd.
Everett, WA
www.snblusa.com
Southern Research
Birmingham, AL
www.southernresearch.org
SRI International
Menlo Park, CA
www.sri.com/biosciences
STEMCELL Technologies Inc.
Vancouver, Canada
www.stemcell.com
AMERICAN COLLEGE OF TOXICOLOGY
Transposagen
Biopharmaceuticals
Lexington, KY
www.transposagenbio.com
Vet Path Services, Inc.
Mason, OH
www.vetpathservicesinc.com
32ND Annual MEETING
2011
WIL Research Company
Ashland, OH
www.wilresearch.com
Xenometrics, LLC
Stilwell, KS
www.xenometricsllc.com
WuXi AppTec, Inc.
Shanghai, China
www.wuxiapptec.com
Zenas Technologies, LLC
Metairie, LA
www.zenastech.com
118
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
AMERICAN COLLEGE OF TOXICOLOGY 2011 COUNCIL
President
Russette Lyons
President-Elect
David Serota
Vice President
Robin Guy
Treasurer
Norman Kim
Secretary
Tracey Spriggs
Past-President
Carol Auletta
Councilor – 2011
Drew Badger
Councilor – 2011
Suzanne Wolford
Councilor - 2011
Grace Furman
119
2011
AMERICAN COLLEGE OF TOXICOLOGY
Councilor - 2012
Lorrene Buckley
Councilor – 2013
David Compton
32ND Annual MEETING
Councilor – 2012
Angelique Braen
Councilor – 2012
James Freeman
Councilor – 2013
Hanan Ghantous
Councilor - 2013
Deborah Novicki
Editor-in-Chief
Mary Beth Genter
120
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
AMERICAN COLLEGE OF TOXICOLOGY – 2011
PRESIDENT
PRESIDENT ELECT
VICE PRESIDENT
Russette M. Lyons, Ph.D.
Head, Education Office
Novartis Institutes for Biomedical Research
250 Massachusetts Avenue
607/913F
Cambridge, MA 02139
T: 617-871-3112
Email: russette.lyons@novartis.com
David G. Serota, Ph.D., DABT
Sr.VP, Drug Safety Development
Sr. Principal Study Director
MPI Research
54943 N. Main Street
Mattawan, MI 49071
T: 269-668-3336 F: 269-668-4151
Email: dave.serota@mpiresearch.com
Robin C. Guy, DABT, MS, RQAP-GLP
Toxicology and GLP Consultant
Robin Guy Consulting, LLC
Preclinical Toxicology & GLP Training
P. O. Box 830
Lake Forest, IL 60045-0830
T: 847-295-9250 F: 847-295-9251
Email: robinguy@robinguy.com
SECRETARY
TREASURER
PAST PRESIDENT
Tracey L. Spriggs, Ph.D., DABT
Director, Toxicology, Worldwide R&D
GlaxoSmithKline
1500 Littleton Road
Parsippany, NJ 07054-3884
T: 973-889-2503 F: 973-889-2469
Email: tracey.l.spriggs@gsk.com
Norman N. Kim, M.S., DABT
Director, Pharmacotoxicology
Biogen Idec, Inc.
10 Cambridge Center
Cambridge, MA 02142
T: 617-679-4995
Email: normankim@biogenidec.com
Carol S. Auletta, MBA, DABT
Director, Program Management
Huntingdon Life Sciences
P. O. Box 2360
Mettlers Road
East Millstone, NJ 08875-2360
T: 732-873-2550 F: 732-873-3992
Email:
aulettac@princeton.huntingdon.com
COUNCILORS – 2011 (only)
Drew A. Badger, Ph.D. DABT
Director - Regulatory Affairs
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320
T: 805-447-5875
Email: dbadger@amgen.com
Grace M. Furman, Ph.D., DABT
President/CEO
Paracelsus, Inc.
128 Daphne Street
Leucadia, CA 92024
T: 760-271-2858
Email: paracelsus.inc@cox.net
Suzanne R. Wolford, Ph.D., DABT
Study Director
Covance Inc.
3301 Kinsman Blvd
Madison, WI 53704
T: 608-242-2721 F: 608-242-2736
Email: suzanne.wolford@covance.com
COUNCILORS - 2010- 2012
Lorrene Alice Buckley, Ph.D., DABT
Research Fellow
Eli Lilly and Company
Lilly Corporate Center
Delaware St - MD 1940
Indianapolis, IN 46285
T: 317- 277-7324 F: 317- 433-0533
Email: buckleyla@lilly.com
Angélique Braen, Ph.D., DABT
Toxicologist
Hoffmann-La Roche, Inc.
340 Kingsland Street
Nutley, NJ 07110
T: 973- 235-3860 F: 973- 235-4710
Email: angelique.braen@Roche.com
121
James J. Freeman, Ph.D., DABT
Distinguished Toxicology Associate
ExxonMobil Biomedical Sciences, Inc.
P. O. Box 971
1545 Route 22 East
Annandale, NJ 08801
T: 908- 730-1123 F: 908- 730-1199
Email: james.j.freeman@exxonmobil.com
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
COUNCILORS - 2010- 2013
David R. Compton, PhD, DABT
Principal Res Investigator-Toxicology
sanofi-aventis U.S. Inc.
1041 Route 202-206 - MC: JR2-103A
P O Box 6800
Bridgewater, NJ 08807-0800
T: 908-541-5328 F: 908-231-2629
Email: david.compton@sanofi-aventis.com
Hanan N. Ghantous, PhD, DABT
Pharma/Toxicologist Supervisor
US FDA
CDER/OAP/DAVP
10903 New Hampshire Avenue
Silver Spring, MD 20993
T: 301-796-0717 F: 301-796-9883
Email: hanan.ghantous@fda.hhs.gov
EDITOR-IN-CHIEF
Mary Beth Genter, Ph.D., DABT
Associate Professor
University of Cincinnati
3223 Eden Ave., ML 670056
144 Kettering Lab
Cincinnati, OH 45267-0056
T: 513-558-6266 F: 513-558-4397
Email: marybeth.genter@uc.edu
122
Deborah L. Novicki, PhD, DABT
Global Head, Toxicology
Novartis Vaccines
350 Massachusetts Avenue
Cambridge, MA 02139
T: 617-871-8206
Email:
deborah.novicki@novartis.com
AMERICAN COLLEGE OF TOXICOLOGY
2011
32ND Annual MEETING
ACT COMMITTEES – 2011
AWARDS COMMITTEE
Robin C. Guy, DABT, RQAP-GLP, MS, Chair
2009-2011
2010-2012
2011-2013
Timothy Jon Raczniak, PhD, DABT
Director, Safety Assessment
Stiefel, a GSK Company
Research & Preclinical Development
20 T. W. Alexander Drive
Research Triangle Park, NC 27709
T:919-624-7203 F: 919-990-6982
Email: timothy.raczniak@stiefel.com
Tracey Zoetis, M.S.
Leigh Ann Burns Naas, PhD, DABT
Managing Consultant
Senior Director
SciLucent, LLC
Pfizer Global R&D
585 Grove Street
Drug Safety Res & Development
Suite 300
10646 Science Center Dr.
Herndon VA 20170
San Diego, CA 92121
T: 703-435-0033 F: 703-435-0440 T: 858-526-4908 F:858-678-8290
Email: tzoetis@scilucent.com
Email:
leighann.burns@pfizer.com
EDUCATION COMMITTEE
Suzanne Wolford, Ph.D., Chair, Lorrene A. Buckley, Ph.D., DABT & Hanan N. Ghantous, Ph.D., DABT, Co-Chairs
2010 -2011
2011 - 2012
Lisa D. Beilke, Ph.D.
Research Scientist II
Gilead Sciences, Inc.
Drug Safety Evaluation
333 Lakeside Drive, Bldg. 324
Foster City, CA 94404
T: 650-522-6361 F: 650-522-5266
Email: lisa.beilke@gilead.com
Anthony Ndifor, PhD
Director
J&J PRD
3210 Merryfield Row
San Diego, CA 92121
T: 858-784-3260 F: 858-450-2026
Email: andifor@its.jnj.com
Timothy Joseph McGovern, Ph.D.
Consultant
Scilucent LLC
585 Grove Street, Suite 300
Herndon, VA 20170
T: 703-435-0033 F: 703-435-0440
Email: t.mcgovern@scilucent.com
Melissa Rhodes, PhD, DABT
Sr. Manager, Sfty Assess.Proj.Dvlpmnt
GlaxoSmithKline
5 Moore Drive
Res Triangle Park, NC 27709
T: 919-483-6908 F: 919-483-0131
Email: melissa.c.rhodes@gsk.com
FINANCE COMMITTEE
Norman N. Kim, DABT, MS, Chair
2009-2011
Steven M. Snyder, M.S.
President
Outsourcing Support Services, Inc.
6569 Braemar Avenue
Noblesville, IN 46062
T: 317-408-0286 F: 317-770-7750
Email: info@outsource-support.com
2010 – 2012
2011-2013
Merrill R. Osheroff, Ph.D.,DABT
President
Osheroff Consulting Services LLC
8418 Parkstone Terrace
Mattawan. MI 49071
T: 269-375-6656 F:269- 375-6656
Email: mroshe@aol.com
123
Ronald J. Christopher, PhD, DABT
Assoc. Vice President
Ambit Biosciences, Inc.
Toxicology & Preclinical Dvlpmnt
4215 Sorrento Valley Blvd.
San Diego, CA 92121
T: 858-334-2137
Email: rchristopher@ambitbio.com
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
MEMBERSHIP COMMITTEE
Angélique Braen, Ph.D., DABT, Chair, James J. Freeman, Ph.D., DABT & Deborah L. Novicki, Ph.D., DABT, Co-Chair
2009-2011
Ted Alan Birkebak, Ph.D., DVM
sanofi-aventis
Drug Safety Evaluation
(JR2-103A)
1041 Route 202-206
Bridgewater, NJ 08870
T: 908-231-3408 F: 908-231-3408
Email: ted.birkebak@sanofi-aventis.com
2010 – 2012
Sandra L. Morseth, Ph.D.
Owner
Morseth Consulting, LLC
4804 Old Middletown Rd
Jefferson, MD 21755
T: 301-473-4730
Email: smorseth@comcast.net
2011 - 2013
Suzanne C. Fitzpatrick, PhD, DABT
Senior Science Advisor
US FDA
office of the Chief Scientist
Office of the Commissioner
10903 New Hampshire Ave WO32
Room 4202
Silver Spring, MD 20993
T: 301-796-8527 F: 301-847-8617
Email:
suzanne.fitzpatrick@fda.hhs.gov
NOMINATING COMMITTEE
Carol S. Auletta, MBA, DABT, Chair
2011
John E. Atkinson, PhD, DABT
Director, Toxicology
Agensys Inc.
2225 Colorado Ave
Santa Monica, CA 90404
T: 310-820-8029 x222
Email: jatkinson@agensys.com
2011
Mary Ellen Cosenza, PhD, DABT, RAC
Executive Director, Emerging Markets
Amgen Inc.
International Regulatory Affairs
1 Amgen Center Drive
Mail Stop 17-2-A
Thousand Oaks, CA 91320-1789
T: 805-447-6318 F: 805-499-9228
Email: mcosenza@amgen.com
OUTREACH COMMITTEE
Carol S. Auletta, MBA, DABT, Chair
2009 – 2011
Alan H. Stokes, Ph.D., DABT
Sr. Scientific Investigator – Toxicology
GlaxoSmithKline
RD9-2136
Five Moore Drive
Res Triangle Pk, NC 27709-3398
T: 919-315-2598 F: 919-483-6858
Email: alan.h.stokes@gsk.com
2010-2012
Alan P. Brown, Ph.D., DABT
Senior Toxicologist
NAMSA
6750 Wales Road
Northwood OH 43619
T: 419-662-4408 F: 419-666-2954
Email: abrown@namsa.com
124
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
2011
PUBLICATIONS COMMITTEE
Mary Beth Genter, Ph.D., Chair
Mary Ellen Cosenza, Ph.D., DABT
Exec. Director, Emerging Markets
Amgen Inc.
1 Amgen Ct. Drive, MS 17-2-A
Thousand Oaks CA 91320-1789
T: 805-447-6318 F: 805-499-9228
Email: mcosenza@amgen.com
Shayne C. Gad, Ph.D., DABT, ATS
Gad Consulting Services
102 Woodtrail Lane
Cary, NC 275118
T: 919-233-2926 F: 919-233-2927
Email: scgad@ix.netcom.com
David W. Hobson, Ph.D., DABT
LoneStar PharmTox LLC
613 Pleasant Valley Drive
Boerne, TX 78006
T: 210-269-6169 F: 830-229-5782
Email: dave@lonestarpharmtox.com
Robert Snyder, Ph.D., ATS
Associate Dean, Research
Rutgers State Univ of NJ
Ernest Mario School of Pharmacy
160 Frelinghuysen Road, Rm. 104
Piscataway, NJ 08854-8020
T: 732-445-2675 x615 F: 732-445-5767
Email: rsnyder@eohsi.rutgers.edu
Norman N. Kim, DABT, MS
Director, Pharmacotoxicology
Biogen Idec, Inc.
10 Cambridge Center
Cambridge, MA 02142
T: 617-679-4995
Email: normankim@biogenidec.com
Tracey Zoetis, MS
Managing Consultant
SciLucent, LLC
585 Grove Street, Suite 300
Herndon, VA 20170
T:703-435-0033 F: 703-435-0440
Email: tzoetis@scilucnet.com
Kenneth L. Hastings, DrPH, DABT, ATS
Associate VP, Regulatory Policy
sanofi-aventis
Corporate Reg Affairs Office
4520 East West Highway, #210
Bethesda, MD 20814
T: 301-771-4267 F: 301-771-4287
Email: Kenneth.hastings@sanofi-aventis.com
Tracey L. Spriggs, Ph.D., DABT
Director, Toxicology, Worldwide R&D
GlaxoSmithKline
1500 Littleton Road
Parsippany, NJ 07054-3884
T: 973-889-2503 F: 973-889-2469
Email: tracey.l.spriggs@gsk.com
PROGRAM COMMITTEE
David G. Serota, Ph.D., DABT, Chair
2009 - 2011
Scott Coleman, Ph.D.
Director Investigative/Mechanistic Tox
Cubist Pharmaceuticals, Inc.
65 Hayden Ave
Lexington, MA 02421
T: 781-860-8643
Email: scott.coleman@cubist.com
Shana Azri-Meehan, Ph.D., DABT
Senior Principal Scientist
Forest Research
Harborside Financial Center – Plaza V
Jersey City, NJ 07311
T: 201-427-8451 F: 201-427-8100
Email: shana.azri-meehan@frx.com
Drew A. Badger, PhD, DABT
Senior Director, Tox & Reg Affairs
Amira Pharmaceuticals
9535 Waples Street, Ste. 100
San Diego, CA 92121
T: 858-228-4688
Email: drew.badger@amirapharm.com
Alan P. Brown, Ph.D., DABT
Senior Toxicology Consultant
Integrated Nonclinical Development Solutions Inc
3005 Miller Avenue
Ann Arbor, MI 48103
T: 734- 929-5392 F: 734- 929-5393
Email: alan.brown@inds-inc.com
125
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Anne Harman Chappelle, PhD, DABT
Chappelle Toxicology Services
3850 Rotherfield Lane
Chadds Ford, PA 19317
T: 484- 844-7662 F: 610- 358-0542
Email: ahchappelle@gmail.com
Kate E Lane, PhD, DABT
Director, Toxicology
Sunovion Pharmaceuticals Inc.
84 Waterford Drive
Marlborough, MA 01752
T: 508-357 7541 F: 508-357 7493
Email: kate.lane@sunovion.com
Robin C. Guy, MS, DABT, RQAP-GLP
Toxicology and GLP Consultant
Robin Guy Consulting, LLC
Toxicology and GLP Training
P. O. Box 830
Preclinical Toxicology & GLP Training
Lake Forest, IL 60045-0830
T: 847- 295-9250 F: 847- 295-9251
Email: robinguy@robinguy.com
Russette M. Lyons, PhD
Head, Education Office
Novartis Institutes for BioMedical Res.
250 Massachusetts Avenue
607/931F
Cambridge, MA 02139
T: 617-871-3112
Email: russette.lyons@novartis.com
Steven Hachtman, MA
Director of Education
Data Sciences International
119 14th Street NW
Saint Paul, MN 55112
T: 651) 481-7400 F: 651) 481-7417
Email: shachtman@datasci.com
Lynnda Reid, PhD
Pharmacology/Toxicology Supervisor
US FDA
CDER- White Oak Bldg. 22
10903 New Hampshire Ave.
Silver Spring, MD 20993
T: 301-796-0984 F: 301-796-9897
Email: lynnda.reid@fda.hhs.gov
Jerry F. Hardisty, DVM
CEO
EPL, Inc.
P. O. Box 12766
Res Triangle Pk, NC 27709
T: 919-998-9407 (ext 600)
Email: jhardisty@epl-inc.com
Melissa Rhodes, PhD, DABT
Sr. Manager, Sfty Assess.Proj.Dvlpmnt
GlaxoSmithKline
5 Moore Drive
Res Triangle Pk, NC 27709
T: 919-483-6908 F: 919-483-0131
Email: melissa.c.rhodes@gsk.com
Nancy Holmes, PhD, DABT
Sr. Program Manager
Battelle
Health & Life Sciences Global Business
505 King Avenue
Columbus, OH 43235
T: 614- 424-3776 F: 614- 458-3776
Email: holmesn@battelle.org
Hilary V. Sheevers, PhD
President, CEO
Aclairo PDG., Inc.
1950 Old Gallows Road,Suite 300
Vienna, VA 22182
T: 703-506-6760 (x307) F: 703-506-0142
Email: hsheevers@aclairo.com
Steven C. Kunder, PhD, DABT
US FDA
CBER
1401 Rockville Pike
Rockville, MD 20852
T: 301-827-6000
Email: steven.kunder@fda.hhs.gov
Tracey Zoetis, MS
Managing Consultant
SciLucent, LLC
585 Grove Street
Suite 300
Herndon, VA 20170
T: 703-435-0033 F: 703-435-0440
Email: tzoetis@scilucent.com
126
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
ACT PAST PRESIDENTS
1979-1980
M. Selikoff (Deceased)
1980-1981
Myron Mehlman, Ph.D.
1981-1982
Yula Bingham, Ph.D.
1982-1983
Arthur Furst, Ph.D., Sc.D. (Deceased)
1983-1984
Gary Flamm, Ph.D.
1984-1985
Ronald W. Hart, Ph.D.
1985-1986
Marshall Steinberg, Ph.D. (Deceased)
1986-1987
Gordon W. Newell, Ph.D.
1987-1988
Robert M. Diener, D.V.M.
1988-1989
Richard M. Hoar, Ph.D.
1989-1990
Carol M. Henry, Ph.D., DABT
1990-1991
Shayne C. Gad, Ph.D., DABT
1991-1992
Mildred S. Christian, Ph.D., ATS (Deceased)
1992-1993
Karen M. MacKenzie, Ph.D., DABT
1993-1994
Richard D. Thomas, Ph.D., DABT
1994-1995
Sharon J. Northup, Ph.D.
1995-1996
Sidney Green, Ph.D.
1996-1997
John A. Thomas, Ph.D.
1997-1998
Christopher P. Chengelis, Ph.D.
1998-1999
David W. Hobson, Ph.D., DABT
1999-2000
Merrill R. Osheroff, Ph.D., DABT
2000-2001
Suzanne C. Fitzpatrick, Ph.D., DABT
2001-2002
Robert E. Osterberg, Ph.D.
2002-2003
John E. Atkinson, Ph.D., DABT
2003-2004
Robert Snyder, Ph.D., ATS
2004-2005
Patricia Frank, Ph.D.
2005-2006
Leigh Ann Burns Naas, Ph.D., DABT
2006-2007
Stephen B. Harris, Ph.D., FATS
2007-2008
A.Wallace Hayes, Ph.D., DABT, FATS
2008-2009
Kenneth L. Hastings, Dr.P.H.
2009-2010
Carol S. Auletta, MBA, DABT
127
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
This activity is supported by educational donations provided by
32ND ANNUAL MEETING SPONSORS – 2011
Aclairo Pharma Dvlpmnt Grp Inc
Vienna, VA
www.aclairo.com
Cubist Pharmaceuticals Inc.
Lexington, MA
www.cubist.com
Altria Client Services, Inc.
Richmond, VA
www.altria.com
Data Sciences International
St. Paul, MN
www.datasci.com
American Petroleum Institute
Washington, DC
www.api.org
Eisai Inc.
Andover, MA
www.eisai.com
Asphalt Institute
Lexington, KY
www.asphaltinstitute.org
Eli Lilly
Indianapolis, IN
www.lilly.com
BASi
West Lafayette, IN
www.bastox.com
EPL, Inc.
Sterling, VA
www.epl-inc.com
Battelle
Columbus, OH
www.battelle.org/hhs/toxicology
ExxonMobil Biomedical Sciences, Inc.
Annandale, NJ
www.exxonmobil.com
BioReliance Corporation
Rockville, MD
www.bioreliance.com
Experimur
Chicago, IL
www.experimur.com
Boehringer Ingelheim
Ridgefield, CT
www.boehringer-ingelheim.com
Flagship Biosciences
Flagstaff, AZ
www.flagshipbio.com
Bristol-Myers Squibb Company
Princeton, NJ
www.bms.com
Forest Research Institute, Inc.
Jersey City, NJ
www.frx.com
Calvert Laboratories
Olyphant, PA
www.calvertlabs.com
GlaxoSmithKline
Research Triangle Park, NC
www.gsk.com
Charles River
Wilmington, MA
www.criver.com
Harlan Laboratories, Inc.
Indianapolis, IN
www.harlan.com
128
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Huntingdon Life Sciences
East Millstone, NJ
www.huntingdon.com
Sage
Thousand Oaks, CA
www.sagepub.com
ISIS Pharmaceuticals, Inc.
Carlsbad, CA
www.isispharm.com
sanofi-aventis US
Bridgewater, NJ
www.sanofi-aventis.com
MPI Research
Mattawan, MI
www.mpiresearch.com
SciLucent, LLC
Herndon, VA
www.scilucent.com
PepsiCo Inc.
Valhalla, NY
www.pepsico.com
Southern Research Institute
Birmingham, AL
www.southernresearch.org
Pfizer Inc.
Groton, CT
www.pfizer.com
WIL Research Company
Ashland, OH
www.wilresearch.com
Ricerca Biosciences
Concord, OH
www.ricerca.com
129
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
32nd ANNUAL MEETING CONSULTANT SPONSORSHIP
William J. Brock, Ph.D., DABT, ATS
Brock Scientific Consulting, LLC
billbrock@comcast.net
John A. Budny, Ph.D.
PharmaCal, Ltd.
jabudny@earthlink.net
Nancy J. Chew, MS, RAC
Regulatory Affairs, North America, Inc.
nchew@ranallc.com
Chris R. Coggins, Ph.D.
Carson Watts Consulting, LLC
chris@carsonwattsconsulting.com
Shayne C. Gad, Ph.D., DABT
Gad Consulting Services
scgad@ix.netcom.com
Elliot B. Gordon, Ph.D., DABT, MS
Elliot Gordon Consulting, LLC
ebgfox@comcast.net
Robin C. Guy, M.S., DABT
Robin Guy Consulting, LLC
robinguy@robinguy.com
William C. Hall, VMD, Ph.D., DACVP
Hall Consulting, Inc.
hallconsulting@earthlink.net
130
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
Stephen B. Harris, Ph.D.
Stephen B. Harris Group
steve@sbjgrp.com
Alan C. Katz, M.S., DABT
toXcel LLC
akatz@toxcel.com
Dennis J. Naas, B.S., PMP®
ProDev Consulting Services, Ltd
dennisnaas@cox.net
Sharon Northup, Ph.D.
Northup RTS
rtsnorthup@aol.com
Vincent J. Piccirillo, Ph.D., DABT
VJP Consulting Inc.
vjpicrilo@aol.com
Steven M. Snyder, M.S.
Outsourcing Support Services, Inc.
info@outsource-support.com
Robert J. Staab, Ph.D.
Regulatory & Technical Associates Inc.
rta1ali1@aol.com
Robert L. Susick, Ph.D., DABT
Susick Consulting, LLC
susick@gmail.com
131
2011
AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
ACT CORPORATE MEMBERSHIP - 2011
Abbott Laboratories, Abbott Park, IL
Allergan, Irvine, CA
Altria Client Services, Inc., Richmond, VA
Amgen Inc., Thousand Oaks, CA
BASi, West Lafayette, IN
Battelle, Columbus, OH
Baxter Healthcare Corporation, Round Lake, IL
Bayer Healthcare Pharmaceuticals, Pine Brook, NJ
Biogen Idec MA, Inc., Cambridge, MA
BioReliance, Rockville, MD
Boehringer Ingelheim, Ridgefield, CT
Bristol-Myers Squibb, PRI, Princeton, NJ
Cantox Health Sciences International, Mississauga, Canada
Charles River, Wilmington, MA
Covance Laboratories Inc., Madison, WI
Data Sciences International, Saint Paul, MN
Eli Lilly and Company, Indianapolis, IN
EPL, Inc., Sterling, VA
Experimur, Chicago, IL
ExxonMobil Biomedical Sciences, Inc., Annandale, NJ
Forest Research Institute, Inc., Jersey City, NJ
Genentech, Inc., South San Francisco, CA
GlaxoSmithKline, Research Triangle Park, NC
Hoffmann-La Roche, Inc., Nutley, NJ
Huntingdon Life Sciences, PRC, East Millstone, NJ
J&J Pharma Co (Centocor/J&J PRD/Tibotec), Radnor, PA
MPI Research, Mattawan, MI
Novartis Pharmaceutical Corporation, East Hanover, NJ
Pfizer Inc., Groton, CT
Purdue Pharma, LP, Cranbury, NJ
R. J. Reynolds Tobacco Co., Winston-Salem, NC
sanofi-aventis US, Bridgewater, NJ
Sequani Limited, Ledbury, United Kingdom
Takeda Global R&D, Lake Forest, IL
WIL Research Company, Ashland, OH
132
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AMERICAN COLLEGE OF TOXICOLOGY
32ND Annual MEETING
UPCOMING MEETINGS
ACT 33rd ANNUAL MEETING
NOVEMBER 4 – 7, 2012
OMNI ORLANDO
CHAMPIONSGATE (Orlando), FL
**************************************
ACT 34th ANNUAL MEETING
NOVEMBER 3 – 6, 2013
JW MARRIOTT HILL COUNTRY
SAN ANTONIO, TX
**************************************
ACT 35th ANNUAL MEETING
November 9 - 12, 2014
HYATT GRAND CYPRESS
ORLANDO, FL
**************************************
133
2011