Antiretrovirals III: Pharmacokinetics and Drug Interactions

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

2. Learning Objectives At the end of this presentation, participants will be able to: • Name the 4 components of pharmacokinetics. • Describe the importance of the liver’s P450 system in drug metabolism. • Name one P450 drug inducer and two P450 drug inhibitors. • Describe the affect Rifampin has on NVP and EFV blood levels. • Describe the affect Rifampin has on Protease Inhibitor (PI) blood levels. • Name 2 different NRTI pairs that should not be prescribed because of drug interactions. 2

3. Outline of Talk • Review of Pharmacokinetics and factors affecting drug absorption, distribution, metabolism, and excretion • Review significance of the cytochrome P450 enzyme system • Highlight important drug interactions in HIV care 3

4. Pharmacokinetics – Definition • 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

5. Drug Absorption Definition - the movement of a drug from its site of administration (stomach, vein, skin) into the bloodstream 5

6. Factors Affecting Drug Absorption • Alterations in gastric pH • some drugs are absorbed better in an acidic environment (Itraconazole, Ketoconazole, Indinivir, Atazanavir) • AIDS patients have low gastric acid production • avoid antacids • other drugs are absorbed better in a higher pH environment (DDI) • Presence or absence of other medications • DDI decreases the absorption of itraconazole, ketoconazole, indinivir (separate administration by at least 1 hour) 6

7. Drug Distribution Definition – Following absorption or systemic administration into the bloodstream, a drug distributes into interstitial and intracellular fluids and then finally into the body tissue. 7

8. Factors Affecting Drug Distribution • Cardiac output and blood flow to organs and tissues • Drug permeability and accumulation in tissues • Protein binding • Most HIV drugs bind to alpha-1 acid glycoprotein or albumin • Protein binding varies among ARVs • NRTIs (except ABC): < 25% • ABC, NVP, IDV: 50-60% • EFV, other PIs: >98% • Protein levels may vary between and within patients 8

9. Drug Metabolism Definition – • The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body. 9

10. 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 and is responsible for the breakdown and clearance of the largest number of drugs; including most PIs and NNRTIs. 10

11. Drug Effects on CYP450 • The activity of the CYP450 enzymes can be affected by many medications. • Drugs that affect CYP450 are categorized as either inducersor inhibitors. 11

12. CYP450 Inducers • Inducerslead to • increased activity of CYP450 • faster breakdown and clearance of other drugs • decreased concentrations of other drugs • Important enzyme inducers include: • Rifampin • NVP • EFV

13. CYP450 Inhibitors • Inhibitorslead to • decreased activity of CYP450 • slower breakdown and clearance of other drugs • increased and prolonged concentrations of other drugs • Important enzyme inhibitors include: • Ritonavir • Ketoconazole • Itraconazole

14. CYP450 Substrates • Drugs that are metabolized by CYP450 (substrates) may be affected by the presence of an inducer or an inhibitor. • Common drugs metabolized by CYP450 include: • NVP • EFV • LPV/r (Aluvia) • Rifampin • Methadone • Ketoconazole • Itraconazole • Clarithromycin & Erythromycin • Simvastatin & Lovastatin • Birth control pills

15. Drug effects on CYP450 • Advantages :The use of the protease inhibitor (PI), Ritonavir (inhibitor) can be used with a second PI to slow down the 2nd PI’s breakdown and clearance. This leads to higher, prolonged blood levels and, decreases the required amount of the 2nd PI. • Disadvantages :The use of Rifampin (inducer) with many ARVs leads to faster breakdown and clearance of these drugs, with unacceptably low blood levels. 15

16. Drug Excretion Definition - • Drugs are eliminated from the body either unchanged or as metabolites. • Kidney - most important organ for drug excretion • Liver-Intestines - substances excreted in the feces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract. 16

17. Factors Affecting Drug Excretion • Renal insufficiency and/or failure • Alkalinization or acidification of urine • Liver failure 17

18. Key Drug Interactions with and within ARVs

19. Rifampin and HIV medications By inducing the Cytochrome P450 enzyme, Rifampin decreases blood levels of: • PI • NNRTI (NVP, EFV) • Methadone • Antifungal Drugs 19

20. Rifampin and ARV blood levels Do not use PI with Rifampin Finch et al. Arch Intern Med 2002;162:985-92 20

21. Rifampin and Nevirapine • RIF decreases NVP levels by 37% • Clinical significance of this interaction is debated. • Some studies demonstrate reduced virological outcomes with the use of NVP-containing ART and RIF-containing TB therapy while others have not. • Possible higher risk of hepatotoxicity with NVP and TB therapy is also a concern.

22. Rifampin and Efavirenz • RIF decreases EFV levels by 25% • This decrease is 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: Conclusions • 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, contra-indicated (1st trimester pregnancy), or not tolerated NVP can be used at standard doses. 23

24. Rifampin and Lopinavir/Ritonavir • 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 dose = RTV dose • LPV 400mg/RTV 400mg twice daily • Aluvia 2 tabs + Ritonavir 3 tabs twice a day • Available by referral to provincial-level OPC

25. Antifungals + ARVs:Fluconazole (FLUC) • FLUC + NVP = ↑ NPV levels • possible increase in hepatotoxicity • monitor closely

26. Antifungals + ARVs:Itraconazole (ITRA) • 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 (Aluvia) = ↑ ITRA levels • Limit ITRA to 200 mg/day

27. Methadone + ARVs

28. Hormonal Contraceptives + ARVs

29. Interactions among NRTIs • DDI + D4T – Avoid combination. • Increased toxicities • D4T + AZT – Avoid combination. • Antagonistic effect; require same enzymes for intracellular phosphorylation • TDF + DDI – Avoid combination. • Increased DDI toxicity • Loss of CD4 responses after time • Suboptimal antiviral response in regimens with EFV 29

30. Recognizing and Avoiding Drug Interactions Review patient’s full medication list at every visit Recognize drugs most commonly associated with interactions (i.e., protease inhibitors, ketoconazole, rifampin, etc) Recognize medications with overlapping toxicities Be aware of 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 • The 4 components of pharmacokinetics are: Absorption, Distribution, Metabolism and Excretion. • The liver’s P450 enzymes are the main components of most drugs metabolized. Drug metabolism is crucial in order for the inactive metabolites to be excreted. • An inducer of the P450 system is Rifampin. Two inhibitors of the P450 system are Ketoconazole and Ritonavir. 32

33. Key Points • Do not use PIs with Rifampin. • In patients on TB therapy, EFV is the preferred NNRTI.NVP can be given if EFV cannot be used. • Antifungal drugs have many potential interactions. Check before prescribing. • Methadone levels are decreased by ART and withdrawal may be precipitated. • Avoid certain NRTI combinations (DDI+D4T, AZT+D4T, DDI+TDF)

34. Thank you! Questions?