Presentation is loading. Please wait.

Presentation is loading. Please wait.

Understanding Pharmacokinetics & Drug-Drug Interactions HIV Research Catalyst Forum April 2010 Kimberly Struble, PharmD FDA Tracy Swan, Treatment Action.

Similar presentations


Presentation on theme: "Understanding Pharmacokinetics & Drug-Drug Interactions HIV Research Catalyst Forum April 2010 Kimberly Struble, PharmD FDA Tracy Swan, Treatment Action."— Presentation transcript:

1 Understanding Pharmacokinetics & Drug-Drug Interactions HIV Research Catalyst Forum April 2010 Kimberly Struble, PharmD FDA Tracy Swan, Treatment Action Group

2 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?

3 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.

4 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

5 PK Definitions 024681012 Time Postdose (hr) 100 1000 10000 Plasma Concentration 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

6 Drug Levels & Resistance

7 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

8 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 Ineffective 0 6 12 18 24 TIME Concentration

9 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

10 3A4 2C19 2D62C9 1A2 2E12A62B62C8 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: 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

11 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)

12 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

13 Harmful Effects Unknown Effects Synergistic/ Beneficial Effects Interpretation of Data

14 Ritonavir “Boosting” Ritonavir “Boosting” Sometimes not good: can lower 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

15 Herbs with Reported Effects on CYP450 St. John’s wort Garlic Ginseng Melatonin Milk thistle Geniposide Scullcap

16 Crixivan and St John’s Wort: Induction 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

17 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

18 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

19 HIV 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:

20 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?

21 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 populations looks for side effects that are rare or from long-term use

22 Integrated test tube and human Approach May reduce number of unnecessary studies Optimize knowledge Metabolism and Drug Interaction Data Benefit/Risk Assessment Key Principles

23 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

24 Preclinical Evaluation Clinical Evaluation Phase 1 - 3Post 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

25 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

26 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

27 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

28 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 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

29 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?


Download ppt "Understanding Pharmacokinetics & Drug-Drug Interactions HIV Research Catalyst Forum April 2010 Kimberly Struble, PharmD FDA Tracy Swan, Treatment Action."

Similar presentations


Ads by Google