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Pharmacokinetics and Drug Interactions

Pharmacokinetics and Drug Interactions. HAIVN Harvard Medical School AIDS Initiative in Vietnam. Learning Objectives. By the end of this session, participants will be able to: Describe 4 components of pharmacokinetics Explain importance of the liver’s P450 system in drug metabolism

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Pharmacokinetics and Drug Interactions

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  1. Pharmacokinetics and Drug Interactions HAIVN Harvard Medical School AIDS Initiative in Vietnam

  2. Learning Objectives By the end of this session, participants will be able to: • Describe 4 components of pharmacokinetics • Explain importance of the liver’s P450 system in drug metabolism • Explain how an inducer and an inhibitor affect the blood level of CYP450 substrates • Describe the most important drug-drug interactions

  3. What is Pharmacokinetics? • The study of how drugs enter, interact with, and leave the body, including: • Absorption • Distribution • Metabolism • Excretion • Or, “what the body does to the drug”

  4. Drug Absorption • The movement of a drug from its site of administration (stomach, vein, skin, etc.) into the bloodstream

  5. Factors Affecting Drug Absorption • Alterations in gastric pH: • some drugs are absorbed better in an acidic environment (itraconazole) • other drugs are absorbed better in a higher pH environment (ddI) • Presence or absence of food or other medications: • Buffered ddI decreases the absorption of itraconazole, ketoconazole, indinivir

  6. Drug Distribution • Following absorption or systemic administration into the bloodstream, a drug distributes into interstitial and intracellular fluids and then finally into the body tissue

  7. Factors Affecting Drug Distribution • Cardiac output and blood flow to organs and tissues • Drug permeability and accumulation in tissues • Protein binding: • Protein binding varies among ARVs • Protein levels may vary between and within patients

  8. What is Drug Metabolism? • The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body

  9. Drug Excretion • Drugs are eliminated from the body either unchanged or as metabolites: • Kidney • Liver-Intestines • Factors affecting drug excretion include: • Renal insufficiency and/or failure • Alkalinization or acidification of urine • Liver failure

  10. Summary of Pharmacokinetics

  11. Role of CYP450 in Metabolism

  12. Cytochrome P450 Enzymes • The cytochrome P450 (CYP) enzyme family is the major enzyme system involved in drug metabolism • CYP-mediated metabolism occurs mostly in the liver • CYP3A is the most important enzyme • responsible for the breakdown and clearance of the largest number of drugs including most PIs and NNRTIs

  13. Drug Effects on CYP450 • Activity of CYP450 enzymes can be affected by many medications • Drugs that affect CYP450 are categorized as either inducers or inhibitors • Drugs that are metabolized by CYP450 (substrates) may be affected by the presence of an inducer or an inhibitor

  14. Examples of CYP450 Inducers and Inhibitors Inducers: Inhibitors: Ritonavir Ketoconazole Itraconazole • Rifampin • NVP • EFV

  15. Examples of Common CYP450 Substrates • ARVs: NVP, EFV, LPV/r (Aluvia) • Rifampin • Methadone • Ketoconazole & Itraconazole • Clarithromycin & Erythromycin • Simvastatin & Lovastatin • Birth control pills

  16. Example: How a CYP450 Inducer affects Substrates Substrates CYP450 Inducer • increased activity of CYP450 • faster breakdown and clearance of other drugs Rifampin • LPV and other PIs, NVP, EFV: • decreased concentrations

  17. Example: How a CYP450 Inhibitor affects Substrates Substrates CYP450 Inhibitor • The 2nd PIs: • increased & prolonged concentrations • decreased activity of CYP450 • slower breakdown and clearance of other drugs Ritonavir

  18. Drug Effects on CYP450 Advantages: • Use of Ritonavir (inhibitor) with another PI leads to: • higher, prolonged blood levels • decreases required amount of 2nd PI Disadvantages: • The use of Rifampin with many ARVs leads to leads to unacceptably low blood levels of these ARVs

  19. Key Drug Interactions with ARVs

  20. Rifampin and HIV Medications • By inducing the CYP450 enzyme, Rifampin decreases blood levels of: • PI • NNRTI (NVP, EFV) • Methadone • Antifungal drugs

  21. Rifampin and ARV Blood Levels Finch et al. Arch Intern Med 2002;162:985-92 Do not use PIs with Rifampin

  22. Rifampin and NNRTIs (1) Rifampin and NVP • NVP levels decreased by 20-58% • Clinical significance of this is debated • Risk of hepatotoxicity with NVP and TB therapy is also a concern Rifampin and EFV • EFV levels decreased by 26% • Not felt to have a significant effect on clinical outcomes • MOH guidelines recommend EFV at standard dosing (600 mg/day) when used with RIF

  23. Rifampin and NNRTIs (2) • In patients on TB therapy, EFV is the preferred NNRTI • Patients on NVP at the time of TB diagnosis should be changed to EFV if possible • If EFV is not available, not tolerated or contraindicated, NVP can be used at standard doses

  24. Rifampin and LPV/r • RIF decreases LPV levels by > 75% **Combination should be avoided if possible • Patients who require RIF-based TB therapy and PI-based ART can be treated with “superboosted” LPV/r • LPV 400 mg + RTV 400 mg twice daily • Available by referral to provincial-level OPC

  25. Case Study: Hung • Hung, a 26 year old HIV-positive man presents to HIV OPC • Has been on ART for about 3 months with AZT, 3TC, NVP • Baseline CD4 count was 67; Hb and ALT normal • Developed pulmonary TB and was recently started on TB therapy (RHEZ) • Should his ART regimen be altered? • If so, how and why?

  26. Antifungals + ARVs: ITRA

  27. Methadone + ARVs Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January 10, 2011.

  28. Hormonal Contraceptives + ARVs

  29. Interactions among NRTIs

  30. How Can You Recognize and Avoid Drug Interactions? • Review patient’s full medication list at every visit • Recognize: • drugs most commonly associated with interactions (PIs, itraconazole, rifampin, etc.) • medications with overlapping toxicities • dietary restrictions with certain medications • Select agents with fewer drug interactions if clinically appropriate • Simplify drug regimens whenever possible

  31. Look it Up!When prescribing a new drug to a patient, always look it up to make sure there aren’t anydrug interactions References: MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS www.HIV-druginteractions.org www.AIDSinfo.nih.gov

  32. Key Points • 4 components of pharmacokinetics • All can affect success of drug therapy • Drug interactions are common when treating PLHIV • Many related to effects of the P450 liver enzymes • Important to recognize and avoid drug interactions

  33. Thank you! Questions?

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