Understanding
Pharmacokinetics &
Drug-Drug Interactions
HIV Research Catalyst Forum
April 2010
Kimberly Struble, PharmD
FDA
Tracy Swan,
Treatment Action Group
TODAY’S TOPICS
• What is pharmacokinetics?
• What is a drug-drug interaction?
– Examples
• How and when are drug interactions studied in
HIV drug development?
– Implications for who is included in clinical trials, and
who is not
• What would YOU do?
What is Pharmacokinetics (PK)?
• Means movement of drugs
• Study of the relationship between
dose, amount of drug in the body
and therapeutic or toxic effects of
a drug
• Pharmacokinetic data help us understand:
– dose and schedule (once a day vs. twice a day,
etc)
– dose adjustments due to drug interactions and
other issues.
Processes that Determine Drug PK
• Absorption: how the drug enters the blood
– The amount of acid in stomach or amount of food changes
the amount of drug absorbed
• This is why some drugs must be taken with or without food or
can not be taken with antacids
• Distribution: how the drug travels in the blood and
how it goes into and out of other areas of the body
• Metabolism: how the body changes a drug usually in
intestine and liver
• Drug Elimination: how the body gets the drug out:
– via kidneys through urine or
– via liver though stool
http://www.thebody.com/content/art875.html
PK Definitions
Cmax: Maximum concentration –
may relate to some side effects
Plasma Concentration
10000
AUC: Area under the curve (filled
area) = overall drug exposure
3000
1000
Cmin: minimum or
trough concentrations:
may relate with efficacy
of HIV drugs
100
0
2
4
6
8
Time Postdose (hr)
http://www.thebody.com/content/art875.html
10
12
Drug Levels & Resistance
What is a Drug-Drug Interaction?
• A drug interaction occurs when
a drug interferes in a
negative (or positive) way
with another drug
• Can increase or lower
drug levels
• Can occur between:
– Two drugs (prescription, over the
counter, vitamins, supplements and
illegal drugs)
– Drugs and foods/drinks
http://www.wisegeek.com/what-is-a-drug-interaction.htm
How Do Drug Interactions
Happen?
They occur due to changes in the pharmacokinetics
of a drug
– Changes in the absorption, distribution, metabolism
and excretion (ADME) of a drug
Concentration
Toxic
Effective
Ineffective
0
6
TIME
12
18
24
Drug Metabolism
• Many drug interactions are due to changes in
drug metabolism:
– How the body changes a drug (usually in
intestines and liver)
– Breaks drug down to make it easer to pass into
urine or stool
Main system involved in drug metabolism
interactions is CYP P450 enzymes found
in liver and intestines
CYP 450 Enzymes
& Drug Interactions with HIV
Meds
Induced by: Norvir, Viracept, Aptivus,
Sustiva, Viramune, Intelence
Inhibited by: Norivir, Viracept, Lexiva,
Kaletra, Crixivan, Invirase, Prezista,
Aptivus
Inhibited by: Aptivus, Prezista, Norvir
3A4
Inhibited by: Aptivus, Intelence,
Sustiva
Inhibited by: Intelence
2C19 2D6
2C9
Induced by: Norvir, Viracept
Induced by: Norvir, Viracept
Induced by: Norvir,
Aptivus, Viracept?
1A2
2E1
2A6
2B6 2C8
Adapted from: thebody.com
Drug Interactions Via Liver
Interactions that happen through CYP enzymes are either
based on enzyme induction or inhibition
Induction:
Drug A induces the body to produce more of
an enzyme which metabolized Drug B
This reduces the amount of drug B, which may lead to
loss of drug B’s effectiveness
Inhibition: Drug A inhibits the production of
enzymes to metabolize Drug B
This increases the amount of Drug B in the body and
could lead to an overdose or toxic effects
– Drugs can be inducers, inhibitors and/or substrates
– Substrates:
• Substance that is acted upon by an enzymes
• Therefore, inducers or inhibitors affects drugs that are substrates
(other drugs can make the substrates drug levels increase or
decrease)
Drug A inhibits the
production of
enzymes to
metabolize Drug B
Inhibition
This reduces
the amount of
Drug B and
may lead to
loss of Drug
B’s
effectiveness
Liver
Induction
Drug A induces the
body to produce more
of an enzyme to
metabolized Drug B
This increases the amount of
Drug B in the body and could
lead to an overdose or toxic
effects
Interpretation of Data
Harmful
Effects
Unknown
Effects
Synergistic/
Beneficial
Effects
Ritonavir “Boosting”
Can be a good thing: less
pills, 60% lower risk of
drug resistance when PI
is boosted
Sometimes not good: can
lower methadone levels,
lead to withdrawal
symptoms
Lima et al; JID 2008; McCance-Katz et al, CID 2003
Herbs with Reported Effects on
CYP450
•
•
•
•
•
•
•
St. John’s wort
Garlic
Ginseng
Melatonin
Milk thistle
Geniposide
Scullcap
Crixivan and St John’s Wort:
Induction Interaction
12
St Johns wort
lowers crixivan and
other protease
inhibitors to
ineffective levels
and can result in
development of
resistance to the
protease inhibitor
Concentration (g/mL)
10
Crixivan
alone
8
6
4
Crixivan +
SJW
2
0
0
1
2
3
Time (hours)
4
5
Piscitelli et
al, Lancet
2000
Illicit Drug Use, per Month
Persons >12 years old
Results from the 2006 National Survey on Drug Use and Health: National Findings
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Substance Abuse and Mental Health Services Administration
HIV Meds & Illicit Drugs / Methadone
Ritonavir
Increases amphetamine levels 2-3 times
Increases “x” levels 5-10 times (one death reported in UK)
Reduces heroin levels by 50%
Methadone
NNRTIS; Sustiva and Viramune (but not Intelence) lower
methadone levels by 40-60%--- methadone dose should be
adjusted
PIs: Lowers methadone levels by 13-50%, depending on the
drug
CCR5 Inhibitor: Selzentry reduces methadone levels by 50%
Marijuana
Lowers levels of atazanavir by up to 60%
Source: Recreational Drugs and HIV Antiretrovirals. A Guide to Interactions for
Clinicians. Produced by New York/New Jersey AETC
HIV Meds & Hormonal Contraceptives
Use caution/additional barrier methods with:
• Prezista
• Lexiva,
• Crixivan
• Kalerta
• Viracept
• Invirase
• Aptivus
• Viramune
• Sustiva
Because hormonal contraceptive levels are reduced and
can led to unintended pregnancy
Source: HIV Drug Interactions, Liverpool HIV Pharmcology Group
Drug Interaction Studies &
HIV Drug Development
Why: are they always necessary?
How: to do them—test tube (in
vitro) or in humans (in vivo)
When: at what point in drug
development should these be
done?
What: drugs should be studied?
Who: will be excluded from
clinical trials until necessary
studies are done?
Drug Development
Phase I:
Pre-clinical:
Phase II:
Small,
Test tube &
short-term, 100s of people,
animal
safety, PK, up to 48 weeks
studies,
safety, dosing,
dose,
look for toxicity drug activity,
how well
does the
healthy
drug work?
volunteers
studied first
Phase III:
1000s of
people,
at least 48
weeks
safety and
efficacy vs.
standard of
care
Phase IV:
postmarketing-larger and
more
diverse
populations
looks for
side effects
that are
rare or from
long-term
use
Key Principles
Metabolism and Drug
Interaction Data
Benefit/Risk Assessment
Integrated test tube and
human Approach
•May reduce number of
unnecessary studies
•Optimize knowledge
Objectives of Drug Interaction Program
Explore if new agent
affects levels of
approved drugs
Understand
how to
avoid
interaction
Determine if any
interactions are
clinically significant to
need dose
adjustment, warning
or contraindication
Understand dose adjustment
Interaction Evaluations
Preclinical
Evaluation
In vitro (test tube):
characterize
metabolism and
which enzymes
are involved
Clinical Evaluation
Phase 1 - 3
Post marketing
In humans: conduct necessary studies to
support dosing of new drug with other anti-HIV
drugs and drugs to treat other common
conditions
Timing of in vivo Drug Interaction
Studies: General Principles
• Amount of data: should be adequate to allow safe conduct of
each phase of development
– 10 day monotherapy study – interaction data not needed
– Phase II/III trials – more data needed
• Number of studies: no specific number needed prior to
approval
– Must be adequate at time of new drug application (NDA) to
support concomitant dosing
– Studies for clinically important but less frequently used
drugs can be conducted post-marketing
• Early discussions with regulatory agencies, community and
investigators can help prioritize conduct of studies
Conclusion
• Early evaluation of in vitro (test tube) drug
metabolism and human drug-drug interactions are
critical for the safe use of combination ARV therapy
• Early identification of potential interactions can:
– Identify studies essential to the overall development process
– Help prioritize clinically important interaction studies
• Appropriate clinical management can lead to more
effective long-term therapy
– Reducing drug toxicity
– Delay development of resistance
What Would You Do?
You are in charge of the company’s drug interaction
strategy and you are about to begin clinical trials with a
new NNRTI, called Big Pharma 123
What do you already know about Big Pharma 123
from test tube studies?
How is it metabolized?
Primarily in the liver, it is a substrate of CYP450- it is not
significantly eliminated through the kidney?
Is it an inhibitor or an inducer?
Big Pharma 123 is an inhibitor
Should we suspect any drug interactions?
123
Drug Interaction Exercise
• Place the following drug interaction studies into
– Phase 1 (4 studies)
– Phase 2 (5 studies)
S = substrate
– Phase 3 (3 studies)
IH = inhibitor
– Phase 4/Post approval
ID = inducer
– Should not perform
Antacids
Lamivudine
Oral contraceptives (S)
Buprenorphine (IH)
Lipitor (S)
Prezista (S, IH)
Efavirenz (S, ID)
Maraviroc (S)
Reyataz (S,IH)
Fentanyl (S)
Methadone (S))
Valtrex (kidney)
Kaletra (S, IH)
Nexium
Viagra (S)
Viread
Explain Your Choices
How did you choose which drugs to study?
Which should be done first (Phase 1, 2) ?
Which need to be done before the drug is approved?
Which can wait until after approval?
What else should be studied?