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  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 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

  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 Concentration Ineffective 0 6 12 18 24 TIME

  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. 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

  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 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 B’s effectiveness • This increases the amount of Drug B in the body and could lead to an overdose or toxic effects

  13. Interpretation of Data Unknown Effects Synergistic/ Beneficial Effects HarmfulEffects

  14. 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

  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 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

  17. Illicit Drug Use, per MonthPersons >12 years old Results from the 2006 National Survey on Drug Use and Health:
 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 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

  20. Drug Interaction Studies & HIV Drug Development Why: are they always necessary? How: to do them—test tube (in vitro) orin 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 II: 100s of people, up to 48 weeks safety, dosing, how well does the drug work? Phase III: 1000s of people, at least 48 weeks safety and efficacy vs. standard of care Phase IV: post-marketing--larger and more diverse populationslooks for side effects that are rare or from long-term use

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

  23. 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

  24. 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

  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 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

  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?