Understanding Understanding Pharmacokinetics &Pharmacokinetics &

Drug-Drug Interactions Drug-Drug InteractionsHIV Research Catalyst ForumHIV Research Catalyst Forum

April 2010April 2010 Kimberly Struble, PharmD Kimberly Struble, PharmD

FDAFDATracy 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

Plas

ma

Con

cent

ratio

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 pharmacokineticsof 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/

mL)

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 FindingsDEPARTMENT OF HEALTH AND HUMAN SERVICESSubstance 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 pregnancySource: 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 ProgramExplore 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?