Understanding Pharmacokinetics

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Understanding Pharmacokinetics Drug-Drug
Interactions

• HIV Research Catalyst Forum
• April 2010
• Kimberly Struble, PharmD
• FDA
• Tracy Swan,
• Treatment Action Group

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• TODAYS 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?

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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.

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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
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PK Definitions
Cmax Maximum concentration may relate to some
side effects
10000
AUC Area under the curve (filled area) overall
drug exposure
3000
1000
Plasma Concentration
Cmin minimum or trough concentrations may
relate with efficacy of HIV drugs
100
0
2
4
6
8
10
12
Time Postdose (hr)
http//www.thebody.com/content/art875.html
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Drug Levels Resistance
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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
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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

Toxic
Effective
Concentration
Ineffective
0 6 12 18
24
TIME
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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

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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 Intelence
Inhibited by Aptivus, Intelence, Sustiva Induced
by Norvir, Viracept
2C19
2D6
2C9
Induced by Norvir, Viracept
1A2
2E1
2A6
2B6
2C8
Induced by Norvir, Aptivus, Viracept?
Adapted from thebody.com
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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 Bs 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)

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Liver
Drug A inhibits the production of enzymes to
metabolize Drug B
Induction
Inhibition
Drug A induces the body to produce more of an
enzyme to metabolized Drug B
This reduces the amount of Drug B and may lead to
loss of Drug Bs effectiveness
This increases the amount of Drug B in the body
and could lead to an overdose or toxic effects
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Interpretation of Data
Unknown Effects
Synergistic/ Beneficial Effects
Harmful Effects
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Ritonavir Boosting
Sometimes not good can lower methadone levels,
lead to withdrawal symptoms

• Can be a good thing less
• pills, 60 lower risk of
• drug resistance when PI
• is boosted

Lima et al JID 2008 McCance-Katz et al, CID 2003
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Herbs with Reported Effects on CYP450

• St. Johns wort
• Garlic
• Ginseng
• Melatonin
• Milk thistle
• Geniposide
• Scullcap

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Crixivan and St Johns Wort Induction Interaction
Crixivan alone
St Johns wort lowers crixivan and other protease
inhibitors to ineffective levels and can result
in development of resistance to the protease
inhibitor
Crixivan SJW
Piscitelli et al, Lancet 2000
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Illicit Drug Use, per MonthPersons gt12 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

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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
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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

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Drug Interaction Studies HIV Drug Development

• Why are they always necessary?
• How to do themtest 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?

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Drug Development
Pre-clinical Test tube animal studies, look
for toxicity
Phase I Small, short-term, safety, PK,
dose, drug activity, healthy volunteers studied
first

Phase III 1000s of people, at least 48
weeks safety and efficacy vs. standard of care
Phase II 100s of people, up to 48 weeks safety,
dosing, how well does the drug work?
Phase IV post-marketing--larger and more
diverse populationslooks for side effects that
are rare or from long-term use
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Key Principles
Integrated test tube and human Approach
Metabolism and Drug Interaction Data

• May reduce number of unnecessary studies
• Optimize knowledge

Benefit/Risk Assessment
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Objectives of Drug Interaction Program
Explore if new agent affects levels of approved
drugs
Determine if any interactions are clinically
significant to need dose adjustment, warning or
contraindication
Understand how to avoid interaction
Understand dose adjustment
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Interaction Evaluations
Preclinical Evaluation
Clinical Evaluation
Phase 1 - 3
Post marketing
In vitro (test tube) characterize metabolism and
which enzymes are involved
In humans conduct necessary studies to support
dosing of new drug with other anti-HIV drugs and
drugs to treat other common conditions
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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

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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

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What Would You Do?

• You are in charge of the companys 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
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Drug Interaction Exercise

• Place the following drug interaction studies into
• Phase 1 (4 studies)
• Phase 2 (5 studies)
• Phase 3 (3 studies)
• Phase 4/Post approval
• Should not perform

S substrate IH inhibitor ID inducer
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
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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?