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

2. 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. 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. 4 Drug Absorption The movement of a drug from its site of administration (stomach, vein, skin, etc.) into the bloodstream

5. 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. 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. 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. 8 What is Drug Metabolism? The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body

9. 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. 10 Summary of Pharmacokinetics 10

11. 11 Role of CYP450 in Metabolism

12. 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. 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. 14 Examples of CYP450 Inducers and Inhibitors Inducers: Rifampin NVP EFV Inhibitors: Ritonavir Ketoconazole Itraconazole

15. 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 16 Substrates CYP450 Rifampin LPV and other PIs, NVP, EFV: decreased concentrations increased activity of CYP450 faster breakdown and clearance of other drugs Inducer

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

18. 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. 19 Key Drug Interactions with ARVs

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

21. 21 Rifampin and ARV Blood Levels SQVIDVNFVLPVNVPEFV Rifampin  84%  89%  82%  75%  37%  25% Finch et al. Arch Intern Med 2002;162:985-92 Do not use PIs with Rifampin

22. 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. 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. 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. 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. 26 Antifungals + ARVs: ITRA Interactive pairResultManagement ITRA + NVP ↓ ITRA levels (↓ AUC by 61%) Monitor closely Consider ↑ ITRA dose ITRA + EFV ↓ ITRA levels (↓ AUC by 39%) Monitor closely Consider ↑ ITRA dose ITRA + LPV/r ↑ ITRA levels Limit ITRA to 200 mg/day

27. 27 Methadone + ARVs ARV EffectComment EFV ↓ methadone levels (by 52%)  Can precipitate withdrawal symptoms  May require increase in methadone dose NVP ↓ methadone levels (by 41%) LPV/r ↓ methadone levels (by 26 to 53%) Opioid withdrawal unlikely but may occur Usually no adjustment in methadone required AZT ↑ AZT levels (by 29-43%)  Monitor for AZT side effects (e.g. anemia) ddI ↓ ddI levels (by up to 50%)  Use with caution  Enteric coated (EC) formulation preferred Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January 10, 2011.

28. 28 Hormonal Contraceptives + ARVs ARV Effect on hormonal contraceptive Comment EFV ↑ ethinyl estradiol Use alternative or additional methods NVP ↓ ethinyl estradiol 20% LPV/r ↓ ethinyl estradiol 42%

29. 29 Interactions among NRTIs NRTI Pair Results of Interaction Recommen- dation DDI + D4T Increased toxicities Avoid combination D4T + AZT Antagonistic effect (require same enzymes for intracellular phosphorylation) TDF + DDI Increased DDI toxicity Loss of CD4 responses after time Suboptimal antiviral response in regimens with EFV

30. 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. 31 Look it Up! When prescribing a new drug to a patient, always look it up to make sure there aren’t any drug interactions References: MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS www.HIV-druginteractions.org www.AIDSinfo.nih.gov

32. 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. 33 Thank you! Questions?