Understanding Understanding Pharmacokinetics &Pharmacokinetics &
Drug-Drug Interactions Drug-Drug Interactions
HIV Research Catalyst ForumHIV Research Catalyst Forum
April 2010April 2010
Kimberly Struble, PharmD Kimberly Struble, PharmD
FDAFDA
Tracy Swan, Tracy Swan,
Treatment Action GroupTreatment 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)?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 PKProcesses 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 DefinitionsPK Definitions
0 2 4 6 8 10 12
Time Postdose (hr)
100
1000
10000
Pla
sma
Co
nce
ntr
atio
n
3000
Cmax: Maximum concentration – may relate to some side effects
AUC: Area under the curve (filled area) = overall drug exposure
Cmin: minimum or trough concentrations: may relate with efficacy of HIV drugs
http://www.thebody.com/content/art875.html
Drug Levels & ResistanceDrug Levels & Resistance
What is a Drug-Drug Interaction?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 How Do Drug Interactions Happen?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
Ineffective
0 6 12 18 24TIME
Con
cent
ratio
n
Drug MetabolismDrug 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
3A4
2C19 2D6 2C9
1A2 2E1 2A6 2B6 2C8
CYP 450 Enzymes CYP 450 Enzymes & Drug Interactions with HIV & Drug Interactions with HIV
MedsMedsInduced by: Norvir, Viracept, Aptivus, Sustiva, Viramune, Intelence
Inhibited by: Norivir, Viracept, Lexiva, Kaletra, Crixivan, Invirase, Prezista, Aptivus
Inhibited by: Intelence
Induced by: Norvir, Viracept
Inhibited by: Aptivus, Prezista, Norvir
Inhibited by: Aptivus, Intelence, Sustiva
Induced by: Norvir, Viracept
Induced by: Norvir, Aptivus, Viracept?
Adapted from: thebody.com
Drug Interactions Via LiverDrug Interactions Via LiverInteractions that happen through CYP enzymes are eitherbased 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)
Liver
Induction
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 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
Harmful Effects
Unknown Effects Synergistic/
Beneficial Effects
Interpretation of Data
Ritonavir “Boosting”Ritonavir “Boosting”
Sometimes not good: canlower methadone levels, lead to withdrawal symptoms
Lima et al; JID 2008; McCance-Katz et al, CID 2003
Can be a good thing: less
pills, 60% lower risk of
drug resistance when PI
is boosted
Herbs with Reported Effects on Herbs with Reported Effects on CYP450CYP450
• St. John’s wort
• Garlic
• Ginseng
• Melatonin
• Milk thistle
• Geniposide
• Scullcap
Time (hours)
0 1 2 3 4 5
Con
cent
ratio
n (
g/m
L)
0
2
4
6
8
10
12
Crixivan and St John’s Wort:Crixivan and St John’s Wort:
Induction InteractionInduction Interaction
Crixivan alone
Crixivan + SJW
Piscitelli et al, Lancet 2000
St Johns wort lowers crixivan and other protease inhibitors to ineffective levels and can result in development of resistance to the protease inhibitor
Illicit Drug Use, per MonthIllicit Drug Use, per MonthPersons >12 years oldPersons >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 / MethadoneHIV Meds & Illicit Drugs / MethadoneRitonavirIncreases amphetamine levels 2-3 timesIncreases “x” levels 5-10 times (one death reported in UK)Reduces heroin levels by 50%
MethadoneNNRTIS; Sustiva and Viramune (but not Intelence) lower methadone levels by 40-60%--- methadone dose should be adjustedPIs: Lowers methadone levels by 13-50%, depending on the drugCCR5 Inhibitor: Selzentry reduces methadone levels by 50%
MarijuanaLowers 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 ContraceptivesHIV Meds & Hormonal Contraceptives
• 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
Use caution/additional barrier methods with:
Drug Interaction Studies & Drug Interaction Studies & HIV Drug DevelopmentHIV 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 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 weekssafety, 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
Integrated test tube and human Approach
•May reduce number of unnecessary studies
•Optimize knowledge
Metabolism and Drug Interaction Data
Benefit/Risk Assessment
Key Principles
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
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
Interaction Evaluations
Timing of in vivo Drug Interaction Timing of in vivo Drug Interaction Studies: General PrinciplesStudies: 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
ConclusionConclusion• 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?What Would You Do?
You are in charge of the company’s drug interactionstrategy and you are about to begin clinical trials with anew NNRTI, called Big Pharma 123
What do you already know about Big Pharma 123from test tube studies?
How is it metabolized?Primarily in the liver, it is a substrate of CYP450- it is notsignificantly 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 ExerciseDrug 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
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
S = substrate
IH = inhibitor
ID = inducer
Explain Your ChoicesExplain 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?