Antiretroviral Drug Interactions

1. Antiretroviral Drug Interactions

2. Disclosure of Financial Relationships Dr. Orrick has received honoraria from Boeringer-Ingelheim and Bristol-Myers Squibb

3. Why are HIV/AIDS Patients at Risk? Use of 3 and 4 drug antiretroviral regimens Multiple agents for treatment/prevention of various opportunistic infections Patient living longer and being treated for other chronic diseases (e.g. diabetes, CAD) Many antiretroviral agents have a profound effect on the cytochrome P450 enzyme system

5. Classifications of Interactions Pharmacokinetic Absorption Acid reducing agents impair atazanavir absorption Distribution TMP/SMX displaces warfarin from protein binding Metabolism Rifampin induces CYP450 metabolism of PIs RTV �boosting� Excretion Pharmacodynamic Additive toxicity Increased bone marrow toxicity of zidovudine (AZT) + ganciclovir Additive/Synergistic CART effect greater than monotherapy Antagonistic Zidovudine (AZT) and stavudine (d4T) reduces antiviral effect

6. Outcomes of Drug Interactions:Beneficial Additive desirable pharmacodynamic effects Combination antiretroviral therapy Use of 2NRTIs + PI or NNRTI ? potency ? resistance PK Boosting ? bioavailability ? pill burden Eliminate food restrictions

7. Outcomes of Drug Interactions: Adverse Toxicity Torsade de pointes: terfenadine, astemizole Rhabdomyolyis: HMG-CoA reductase inhibitors Hypotension: calcium channel blockers, erectile dysfunction agents Excessive sedation/respiratory depression: benzodiazepines Drug resistance Therapeutic failure

8. NRTI Drug Interactions Zidovudine: Agents that cause additive bone marrow suppression (i.e. ganciclovir, flucytosine, pentamidine) Antagonism with stavudine (competition for intracellular activation) Didanosine (ddI): Inhibition of absorption of other agents due to ddI buffer in Videx� (FQs, tetracyclines, dapsone, ketoconazole, indinavir, delavirdine) Ribavirin significantly ? ddI levels-do not use together

9. NRTI Drug Interactions Didanosine, Stavudine, Zalcitabine Agents causing additive neurotoxicity (vincristine, cisplatin, isoniazid) Agents causing additive pancreatoxicity (alcohol, pentamidine, valproic acid) Ribavirin-do not use with didanosine Abacavir Metabolized by alcohol dehydrogenase (alcohol can increase abacavir levels and toxicity)

10. Tenofovir (TDF, Viread�) Drug Interactions ? ddI levels (Videx� and Videx EC�) ? 60 kg: Videx EC? 250 mg with TDF 300 mg qd co-administered with/without food < 60 kg: Videx EC? 200 mg with TDF 300 mg qd co-administered with/without food ? atazanavir levels Boost ATV (300 mg qd + RTV 100 mg qd) when given with TDF

11. Cytochrome P450 (CYP) Enzyme System Substrate: metabolized by enzyme Inhibitor: inhibits metabolism of substrate Inducer: induces metabolism of substrate through increased production of enzyme Interactions involving induction may be delayed since new enzyme must be synthesized Some drugs may have properties of all 3: efavirenz

12. Enzyme/Substrate Interaction

13. Enzyme/Substrate Interaction

14. Enzyme Inhibition

15. Enzyme Induction

16. Effect of ARVs on Drug Metabolism Professor Back explained that this pyramid demonstrates the activity of the cytochrome P450 enzyme family with respect to the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). �Antiretrovirals can be inducers or inhibitors of these enzymes�, he commented. CYP3A4, the most important cytochrome P450, is induced by ritonavir (RTV), nelfinavir (NFV), efavirenz (EFV) and nevirapine (NVP). In contrast, it is inhibited by RTV, NFV, indinavir (IDV), amprenavir (APV), saquinavir (SQV), and delavirdine (DLV). The other cytochrome P450s include 2CI9, 2D6, 2C9, 1A2, 2E1, 2A6, 2B6, 2C8. They are variously inhibited or induced by antiretroviral drugs as shown on the slide. Nevirapine induces cytochrome P450 3A4 and cytochrome 2B6.Professor Back explained that this pyramid demonstrates the activity of the cytochrome P450 enzyme family with respect to the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). �Antiretrovirals can be inducers or inhibitors of these enzymes�, he commented. CYP3A4, the most important cytochrome P450, is induced by ritonavir (RTV), nelfinavir (NFV), efavirenz (EFV) and nevirapine (NVP). In contrast, it is inhibited by RTV, NFV, indinavir (IDV), amprenavir (APV), saquinavir (SQV), and delavirdine (DLV). The other cytochrome P450s include 2CI9, 2D6, 2C9, 1A2, 2E1, 2A6, 2B6, 2C8. They are variously inhibited or induced by antiretroviral drugs as shown on the slide. Nevirapine induces cytochrome P450 3A4 and cytochrome 2B6.

17. NNRTI Drug Interactions All NNRTIs are metabolized by the CYP3A4 enzyme (EFV also metabolized by 2B6) Delavirdine can inhibit CYP3A4 enzyme Nevirapine can induce CYP3A4 Efavirenz can inhibit or induce CYP3A4 enzyme

18. PI Drug Interactions All PIs are metabolized all or in part by the CYP3A4 enzyme system All PIs can inhibit CYP3A4 enzymes Ritonavir most potent inhibitor Saquinavir least potent inhibitor Ritonavir can also induce CYP1A2, CYP 2C9, CYP3A4

19. Drugs That Should Not Be Given With PIs Simvastatin Lovastatin Astemizole Terfenadine Cisapride Pimozide Bepridil St. John�s Wort Rifampin (except ritonavir) Rifapentine Midazolam Triazolam Ergot alkaloids

20. Inhibitors of Drug Metabolism Protease inhibitors Delavirdine Efavirenz Fluconazole Itraconazole Ketoconazole Voriconazole Isoniazid Ciprofloxacin Clarithromycin Erythromycin Diltiazem Verapamil Amiodarone Cimetidine Omeprazole Fluoxetine Grapefruit juice

21. Inducers of Drug Metabolism Nevirapine Efavirenz Ritonavir Rifampin Rifabutin Phenobarbital Carbamazepine Phenytoin

22. Atazanavir (Reyataz�) with Acid-reducing Agents) Dosing must be separated by 2 hours from traditional antacids (e.g. calcium carbonate (Tums�) Take 2 hours before or 10 hours after H-2 blockers (e.g. famotidine, Pepcid�; nizatidine, Axid�) Should not be used with proton pump inhibitors (PPIs) (e.g. omeprazone, Prilosec�; pantoprazole, Protonix�)

23. Interaction Between Atazanavir + Omeprazole N = 48 HIV(-) subjects ATV exposures substantially reduced by coadministration with OMP 40 mg Not corrected by increased ATV dose or 8 oz cola OMP exposures not significantly altered Effect of OMP 20 mg (OTC dose) not known Do not coadminister Data were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston in April 2005 on the interaction between atazanavir (ATV) and omeprazole (OMP), showing the fairly dramatic reduction in atazanavir levels. In orange, you see atazanavir trough concentrations in patients receiving atazanavir/ritonavir 300/100 mg once daily without omeprazole. When 40 mg of omeprazole is coadministered with atazanavir/ritonavir 300/100 mg once daily, with (grey line) or without (blue line) cola�which was believed to perhaps have a mitigating effect in terms of also providing this acidic microenvironment� you see fairly substantial reductions in atazanavir concentrations, with no benefit of cola. Whether or not the same effect is seen with the 20 mg over-the-counter dose of omeprazole is not known. Dr. Fletcher recommends that you do not coadminister 20 mg omeprazole with atazanavir unless perhaps you had some availability of knowing what the concentrations absolutely are, for instance through Therapeutic Drug Monitoring. For more information on this study, go online to: http://clinicaloptions.com/hiv/conf/croi2005/cs/658.asp Data were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston in April 2005 on the interaction between atazanavir (ATV) and omeprazole (OMP), showing the fairly dramatic reduction in atazanavir levels. In orange, you see atazanavir trough concentrations in patients receiving atazanavir/ritonavir 300/100 mg once daily without omeprazole. When 40 mg of omeprazole is coadministered with atazanavir/ritonavir 300/100 mg once daily, with (grey line) or without (blue line) cola�which was believed to perhaps have a mitigating effect in terms of also providing this acidic microenvironment� you see fairly substantial reductions in atazanavir concentrations, with no benefit of cola. Whether or not the same effect is seen with the 20 mg over-the-counter dose of omeprazole is not known. Dr. Fletcher recommends that you do not coadminister 20 mg omeprazole with atazanavir unless perhaps you had some availability of knowing what the concentrations absolutely are, for instance through Therapeutic Drug Monitoring. For more information on this study, go online to: http://clinicaloptions.com/hiv/conf/croi2005/cs/658.asp

24. Interactions with Lipid Lowering Agents Simvastatin and lovastatin are contraindicated with PIs or the NNRTI delavirdine Pravastatin and fluvastatin least likely to interact with ARVs Use atorvastatin at low-doses with caution (AUC ? 71% with NFV, 5-fold with lopinavir/ritonavir) Rosuvastatin does not rely on CYP3A4 for metabolism-? Interaction with ARVs

25. PI Interactions with Statins

26. Statin/PI Interactions

27. Statin/PI Interactions (cont�d)

28. Statin/NNRTI Interactions

29. Fluticasone induced Cushing�s Syndrome Fluticasone is a 3A4 substrate and RTV a 3A4 inhibitor

30. Interactions with Mental Health Medications

31. Antidepressants Most metabolized at 2D6 Exceptions: Fluvoxamine (Luvox�) AVOID Nefazodone (Serzone�) AVOID Bupropion (Wellbutrin�, Zyban�) dose cautiously with ritonavir But you can memorize a few Key interactions. Avoid: Luvox, Serzone and be cautious with high dose Wellbutrin (could lower seizure threshold).But you can memorize a few Key interactions. Avoid: Luvox, Serzone and be cautious with high dose Wellbutrin (could lower seizure threshold).

32. Antidepressants SSRIs Fluoxetine (Prozac�) & paroxetine (Paxil�, Pexeva�): some interactions, but not generally clinically significant Citalopram (Celexa�), escitalopram (Lexapro�), & sertraline (Zoloft�): have fewest interactions Tricyclic antidepressants Most are metabolized all or in part by 2D6 Ritonavir can inhibit 2D6 metabolism and increase levels of TCAs The cleanest SSRI�s are those listed at the bottom of the slide � Prozac & Paxil have interactions at P450, but more of a concern with anticoagulation than with HAART.The cleanest SSRI�s are those listed at the bottom of the slide � Prozac & Paxil have interactions at P450, but more of a concern with anticoagulation than with HAART.

33. Antidepressants Dual-action agents: Venlafaxine (Effexor�) & duloxetine (Cymbalta�) Well tolerated without adjusting dose Mirtazipine (Remeron�) Well tolerated, although some 3A4 metabolism Trazodone (Deseryl�) Levels can be increased by 3A4 inhibitors, start with low dose and titrate slowly Need to adjust dose of Effexor with impaired hepatic metabolism, but no specific medication interactions. Recent updates on Cymbalta indicate caution in use with impaired hepatic function (e.g. Hepatitis C or Alcoholic Cirrhosis) � Cymbalta is also metabolized at 2D6.Need to adjust dose of Effexor with impaired hepatic metabolism, but no specific medication interactions. Recent updates on Cymbalta indicate caution in use with impaired hepatic function (e.g. Hepatitis C or Alcoholic Cirrhosis) � Cymbalta is also metabolized at 2D6.

34. Anxiolytics Anxiolytics Mostly metabolized at 3A4 Avoid Triazolam (Halcion�) Midazolam (Versed�) Because of action at 3A4, never use the sulfonated benzos: Xanas, Halcion or Versed (popular in anesthesia). The effective blood level will be dramatically elevated.Because of action at 3A4, never use the sulfonated benzos: Xanas, Halcion or Versed (popular in anesthesia). The effective blood level will be dramatically elevated.

35. Anxiolytics Anxiolytics Safest to use glucuronidated benzodiazepines: Lorazepam (Ativan�) Temazepam (Restoril�) Oxazepam (Serax�) Caution with buspirone (Buspar�), and dosing of other benzodiazepines with ART (3A4) Prefer to use glucuronidated benzos � least risk on an interaction. Buspar is metabolized at 3A4 and can also be elevated by ART � use caution in dosing � otherwise more likely to encounter side effects.Prefer to use glucuronidated benzos � least risk on an interaction. Buspar is metabolized at 3A4 and can also be elevated by ART � use caution in dosing � otherwise more likely to encounter side effects.

36. Antipsychotics When used with ritonavir, start with low dose: 1A2 & 2D6 Haloperidol (Haldol�) (risk EPS & TD) Avoid chlorpromazine (Thorazine�), thioridazine (Mellaril�) Olanzapine (Zyprexa�), clozapine (Clozaril�), risperidone (Risperdal�) 3A4 Aripiprazole (Abilify�), ziprasidone (Geodon�), quetiepine (Seroquel�) clozapine (Clozaril�) Avoid pimozide (Orap�) Really should avoid the typicals or 1st generations completely because of increased risk of Tardive Dyskinesia (irreversible) in HIV. Clozaril is relatively contraindicated anyway because of (allergic) agranulocytosis risk. Really should avoid the typicals or 1st generations completely because of increased risk of Tardive Dyskinesia (irreversible) in HIV. Clozaril is relatively contraindicated anyway because of (allergic) agranulocytosis risk.

37. Stimulants Atomoxetine (Strattera�*) * = nonstimulant Caution with impaired hepatic function Metabolized at 2D6 Inhibits at 2D6 Modafinil (Provigil�) � be cautious Metabolized at 3A4 Induces at 1A2 & 3A4 Strattera: Some reported cases of hepatic failure, but heralded with classic jaundice and reversible in those cases reported. Provigil is the most popular of new medications. It is a stimulant but uses other, essentially unknown mechanism. Be very careful with dosing. Little is known with this medication � heavily marketed�.Strattera: Some reported cases of hepatic failure, but heralded with classic jaundice and reversible in those cases reported. Provigil is the most popular of new medications. It is a stimulant but uses other, essentially unknown mechanism. Be very careful with dosing. Little is known with this medication � heavily marketed�.

38. Rifamycins with PIs and NNRTIs �Updated Guidelines for the Use of Rifamycins for the Treatment of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors�-January 20, 2004 www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

39. Rifamycins with PIs and NNRTIs Rifamycins can induce CYP3A4 enzyme and significantly ? PI and NNRTI levels Rifampin > rifapentine* > rifabutin Data has supported the use of rifampin with certain ARV combinations All single PIs should not be used with rifampin (except ritonavir-rarely used as single PI today) Rifabutin is also a substrate for CYP3A4 and its levels can be affected by PIs and NNRTIs

40. Co-administration of Rifampin with PIs

41. Co-administration of Rifampin with NNRTIs

42. Rifabutin Use with PIs

43. Rifabutin Use with PIs

44. Rifabutin Use with NNRTIs

45. Patient Case MJ CF is a 58 yo male diagnosed with HIV in June of 2003, he returns to the clinic for routine follow up of his HIV. He was started on ARVs in August 2004 (CD4 220, viral load 158,000 at that time) Current Meds: lamivudine/abacavir (Epzicom�) 1 tab po qd, atazanavir (Reyataz�) 300 mg po qd, ritonavir (Norvir�) 100 mg qd, lisinopril 10 mg po qd, ezetimibe/simvastatin (Vytorin�) 10/40 mg po qd, metformin 500 mg po bid

46. Patient Case MJ He was recently discharged from the hospital at NFRC where he was treated for pneumonia. Additional medications on discharge: pantoprazole 40 mg po qd, moxifloxacin 400 mg po qd Viral load: < 50 copies/mL, CD4+ cell count 345 cells/mm3 (3 months ago) Recent labs show a total bilirubin of 3.8 mg/dL

47. Patient Case MJ Which medication is likely causing the patient�s hyperbilirubinemia? Lamivudine (component of Epzicom�) Abacavir (component of Epzicom�) Atazanavir (Reyataz�) Simvastatin (component of Vytorin�)

48. Patient Case MJ Which medication(s) should be discontinued due to a significant drug interaction with the patients ARVs? Metformin Simvastatin Pantoprazole Moxifloxacin

49. Drug Interaction Resources www.hiv-druginteractions.org www.hivinsite.ucsf.edu www.aidsinfo.nih.gov(DHHS HIV Treatment Guidelines, TB Guidelines)