Use of healthy male volunteers in bioequivalence studies
of antineoplastic drugs: a pivotal study with
capecitabine
Gilberto De Nucci
Department of Pharmacology, Faculty of Medical Sciences, State University of
Campinas (UNICAMP), Campinas, São Paulo, Brazil
Capecitabine
• Capecitabine is an adjuvant treatment for colon cancer and for
the treatment of metastatic breast cancer in patients whose
pathology did not improve during treatment with other
therapeutic agents.
• Capecitabine is a prodrug, and it is selectively activated by
tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine
phosphorylase, which is generally expressed at high levels in
tumors.
Capecitabine
• Clinical and pharmacokinetics studies for capecitabine are
performed in patients with cancer.
• Standard dosing is 1,250 mg/m2 orally twice daily, morning
and evening, for 14 consecutive days in 3-week cycles.
• For an average healthy male volunteer weight (70 kg) and
height (170 cm) this would mean 2150 mg per dose (4300 mg
per day). Corporal Area = 1,809 m2
Metabolic activation of capacitabine in humans
Reiner et al, 1998
Adverse effects
• Asthenia/ fatigue
• Diarrhea
• Lymphopenia
• Leukopenia
• Mucositis
• Nausea
• Neutropenia
• Thrombocytopenia
• Vomit
• Hand Foot Syndrome
April 10th, 2010
Committee of Ethics in Research approval the pilot study protocol
Item V- CER evaluation
The Committee of Ethics in Research of the Faculty of Medical Sciences of
UNICAMP, obeying the evaluations of the previously designated members
for the present case and attending all of dispositions of Resolutions
196/96 and complementary, decided to approve without restrictions the
Research Protocol, the informed consent, as well as all the attached files
included in the research proposal.
June 6th 2011
2nd World Congress on Bioavailability
& Bioequivalence 2011 (BABE 2011)
Presentation of the results of the two pilot studies of
capecitabine on 16 healthy male volunteers
National Commission on Ethics in Research (CONEP)
August 10th 2011
CONEP had received from the National Agency of Sanitary Vigilance
(ANVISA) a note warning about the approval from the Committee of
Ethics in Research of clinical studies that violated the ethical concepts of
resolution CNS 196/96.
In response, CONEP released a note stating the following:
“Healthy individuals should not enroll on bioequivalence studies of drugs
with high toxic potential (chemotherapeutics); Studies with these agents
should only be performed on patients that may benefit from the studied
drug.”
- Evaluated the safety of a capecitabine bioequivalence study (150 mg tablet) using 8
healthy male volunteers under fasting and non-fasting conditions.
- The study was initially conducted with an open, randomized, two-period crossover
design in a 2-week washout with fasted volunteers.
- After the fasted study a new protocol was submitted to the Ethics Committee to
evaluate the non-fasted study.
- The volunteers were selected for the study after having their health status previously
assessed by a clinical evaluation and laboratory tests .
- A single capecitabine tablet (150mg) was given in each interment.
- The drug was well tolerated by the volunteers, and they presented no adverse
reactions. The biochemical and hematological parameters presented no clinically
relevant alterations.
- Results indicate that it is safe to perform capecitabine bioequivalence studies in
healthy male volunteers.
Technical Note 05/2012
Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment I
must respect the general measures described on this note as well as specific measures to each
drug described on the same attachment.
Item 3.1 – Based on the toxic potential of these drugs the investigators must decide on the
participation of patients or healthy volunteers, as well as the most adequate dose to use in the
study.
Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted
accordingly to this note
Capecitabine
Study population
Oral dose
Male volunteers
Female volunteers with definitive sterilization
150 mg
Technical Note 06/2012
Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment I
must be conducted on patients of the target population of the studied drug; patients must be
receiving treatment to a pathology to which the reference drug is indicated. These studies
must respect the technical aspects depicted on this note.
Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted
on patients.
Azacitidine
Ganciclovir
Temozolomide
Chlorambucil
Goserelin
Testosterone
Clozapine
Leuprorelin
Topotecan
Doxorubicin
Melphalan
Triptorelin
Etoposide
Mercaptopurine
Vorinostat
Everolimus
Nabilone
Felbamate
Nilutamide
European Medicines Agency
December 13th, 2012
6.2.1. Phase I, single agent dose and schedule finding trials
– Non-clinical data and, when available, data from healthy volunteers
should be used to design the studies to be conducted in patients
– Based on preclinical tolerability and toxicology findings and the
assumed pharmacology of the compound, early trials may sometimes
be conducted in healthy volunteers.
Objective
To evaluate bioequivalence between two
formulations of capecitabine (test and reference)
in healthy male volunteers
Why evaluate on healthy volunteers?
Capecitabine is employed for the treatment of metastatic
cancer, therefore the prognosis of these patients is usually
reserved. To expose these critical patients to either
ineffective or toxic doses of the drug (due to unforeseen
infra or supra-bioavailability of the test formulation), to
experimental procedures such as internment, venous
puncture and blood collection to evaluate bioequivalence
should be ethically re-evaluated. Furthermore, studies
performed in patients are with therapeutic doses, using
several tablets for each administration (generally a
combination of both 150 and 500 mg tablets), a procedure
that limits the discrimination between dosage forms.
Methods
• The clinical protocols were approved by the university IRB.
• The studies were conducted using an open, randomized, twoperiod (150 mg single administration of Xeloda; F. Hoffmann-La
Roche Ltd., vs a test formulation) crossover design with a oneweek washout interval, in two groups, with food.
• All male subjects were negative for HIV, HCV and HBV. The
laboratory tests (biochemical and hematological parameters) were
performed on average three days after the first confinement, and
7 days after the second confinement.
Methods
• Subjects: Seventy-two healthy male volunteers were recruted
• Hematological
evaluation:
Hemoglobin,
Hematocrit,
Erythrocyte Count, VCM, HbCM, White Cell and Platelet
Count
• Biochemistry: Total Cholesterol, Triglycerides, Total Proteins,
Albumin, Uric Acid, Total Bilirubins (Direct and Indirect),
Alkaline Phosphatase, SGOT (AST), SGPT (ALT), Urea,
Creatinine, Fasting Blood Glucose
• Physical exam and EKG.
Methods
• Dose: 150mg single-dose on each treatment with a one-week
washout period between treatments.
• Volunteers had a standardized breakfast 30 minutes before drug
administration.
• Blood samples were collected at 0:10, 0:15, 0:20, 0:30, 0:40, 0:50,
1:00, 1:10, 1:20, 1:30, 1:40, 1:50, 2:00, 2:30, 3:00, 3:30, 4:00,
5:00, 6:00 and 7:00h after drug administration
Determination of Capecitabine
• HPLC coupled to tandem mass spectrometry
• Deuterated capecitabine
Capecitabine
M.W. 359.93 g/mol
Capecitabine-d11
M.W. 371.08 g/mol
Results
• Three drop-outs due to time unavailability.
• The drug was well tolerated by the 69 volunteers that
concluded the study.
• One volunteer had a mild headache.
• Three individuals presented hypertriglyceridemia.
Results
• To determinate if hypertriglyceridemia was due to capecitabine,
plasma samples remaining from the analitical study were evaluated for
triglycerides.
• Two out of the 3 volunteers had hypertriglyceridemia before the first
and the second dose of capecitabine, and did not have significant
variation through out the treatment day.
• The volunteer that had normal triglycerides before treatments only
presented mildly elevated levels (273 mg/dL) 8 days after the second
dose (discharge evaluation). It resolved without treatment, as
evaluated 30 days after the last dose.
Conclusion
It is safe to perform capicetabine (150mg) bioequivalence
study in healthy male volunteers.
Use of male volunteers in bioequivalence studies of antineoplastic drugs: a pivotal study with capecitabine.
Acknowledgments to the
Galeno Analytical Unit Team
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André Borges – Quality Assurance
Antonio Sergio Silveira – Analyst
Guilherme Pellegatta – Administrative Supervisor
Gustavo Mendes - BioStatistical Manager
Jaime O. Ilha – Coordinator
Lu Shi Chen – Analytical Manager
Marinalva Sampaio – Clinical Manager
Tainah Babadópulos Magalhães – Quality Manager
Thiago Gagliano – Clinical investigator