1. 1 To Use Them Together or Not Understanding Drug Interactions With HCV Medications Rajwant Minhas, FH Resident HIV/AIDS Rotation May 2012

2. 2 Objectives Understand principles of drug interactions Become aware of drug interactions of HCV medications with: –Antiretrovirals –Antidepressants –Statins –Antihypertensives –Contraceptives and hormonal replacement –Methadone –Steroids

3. 3 Drug-Time Concentration Curve Source: http://www.skepticnorth.com/2012/01/generic-drugs-should-we-be-skeptical/

4. 4 How Are Drugs Eliminated From Body? Renal: Excreted unchanged in the urine. Clearance directly proportional to renal function Probenecid: Drug that blocks renal excretion of other drugs Patrick D. Drug Metabolism. University of Texas Pharm 143M Class Notes. Fall 2008

5. 5 Drug Metabolism Liver: Primary site for drug metabolism Mediated by Cytochrome P-450 system present in liver and enterocytes of small intestine Image Source: http://www.nature.com/nrd/journal/v1/n1/fig_tab/nrd705_F1.htmlhttp://www.nature.com/nrd/journal/v1/n1/fig_tab/nrd705_F1.html Patrick D. Drug Metabolism. University of Texas Pharm 143M Class Notes. Fall 2008

6. 6 Drug Metabolism Drug metabolism: Chemical transformation of drug by enzymatic systems Goal: –To de-toxify drugs, and –Make them either more water soluble (for excretion in urine) or more fat soluble (for excretion in the bile, and then into the feces). –Hydrosoluble molecules: Low toxicity risk  ↑ renal excretion –Lipophilic drugs  Hydrophilic Metabolites Patrick D. Drug Metabolism. University of Texas Pharm 143M Class Notes. Fall 2008

7. 7 CYP450 The P450 cytochromes chemically oxidize or reduce drugs > than 25 human cytochrome P450’s They are named by number and letter: –4 major families  indicated by number –6 major sub-families  indicated by letter –Individual enzymes within a subfamily  indicated by number For example 3A4, 2D6, 2C19 Badea G. Drug Metabolism. Feb 2007

8. 8 CYP450 System Badea G. Drug Metabolism. Feb 2007

9. 9 P-glycoprotein Transports drugs out of the cell Tissue expression is varied Found in the major absorption, distribution and elimination organs P-gp inducers and inhibitors\ Source: http://www.nature.com/nrc/journal/v2/n6/images/nrc823-f3.gif

10. 10 Drug Interactions Pharmacokinetic Interactions: –Inhibition of metabolism –Induction of metabolism –Altered drug absorption –Inhibition of renal excretion –Displacement from plasma protein binding sites Pharmacodynamic Interactions: –Synergism or antagonism of drug effects, without alterations in concentrations of either drug Badea G. Drug Metabolism. Feb 2007

11. 11 Examples of Drug Interactions Drug interactions involving oral medications can take place in at least 2 sites: the liver and the intestine. Drug Inhibition: –Saquinavir + ritonavir: Inhibition of CYP 3A4 20 fold ↑ in plasma concentration Drug Induction: –Phenytoin + Lopinavir/Ritonavir: Multi-agent interaction, mechanism unclear. Both phenytoin and ritonavir are drug inducers, ritonavir is a drug inhibitor too 30% lower lopinavir AUC 35% lower ritonavir AUC 23% lower phenytoin AUC Pharmacodynamic Interaction: –Enhanced bone marrow suppression in patients given concurrent zidovudine and ganciclovir Lexicomp. Kiser JJ et al. Hepatology 2012;55:1620-1628.

12. 12 But How Do I Find All This Information?

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16. 16 hep-druginteractions.org/

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21. 21 BOC and TVR Pharmacokinetics BOC: Metabolized by CYP3A4, CYP3A5 and aldoketoreductases –Strong reversible inhibitor of CYP3A4 and p- glycoprotein –Protein binding 75% TPV: Substrate and strong inhibitor of CYP3A4 and p-glycoprotein –Protein binding 59-76% Kiser JJ et al. Hepatology 2012;55:1620-1628.

22. 22 Drug Interactions With BOC & TPV Rifampin: Potent CYP3A4 inducer –Reduced the single dose TPV AUC and Cmax by 92% and 86% Ketoconazole: A potent CYP3A inhibitor – Increased single dose TPV AUC and Cmax by 62% and 24% after a single dose of ketoconazole TPV increased digoxin Cmax and AUC by 1.5 and 1.85 fold –Lower doses may be required, monitor digoxin levels Kiser JJ et al. Hepatology 2012;55:1620-1628.

23. 23 Drugs to Avoid or Use With Caution in Patients on BOC or TPV Anxiolytics and Sleep Aids Antidepressants Antihypertensive Agents Antipsychotics Drug addiction support medications Immunosuppressants Opioid Replacements Oral Contraceptives Statins Kiser JJ et al. Hepatology 2012;55:1620-1628.

24. 24 Protease Inhibitors With Statins : Contraindicated, potential for myopathy including rhabdomyolysis : A lower maintenance dose may be warranted, with additional clinical monitoring StatinBoceprevirTelaprevir Atorvastatin Lovastatin Simvastatin Rosuvastatin Pravastatin Hep-druginteractions.org Tseng A. Toronto General Hospital April 24, 2012

25. 25 TPV + Atorvastatin Mean plasma concentration-time profile of atorvastatin following oral administration with and without telaprevir. Error bars represent the standard error of the mean. Lee JE et al. Antimicrob Agents Chemother. 2011 October; 55(10): 4569–4574. Combination contraindicated

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27. 27 Opioid Replacements MethadoneBuprenorphine 85% plasma protein bound Metabolized by CYP3A, 2C8 and glucuronidation TPV displaces methadone from its plasma protein binding sites But free concentrations were unchanged A methadone dose adjustment likely unnecessary with the addition of TPV BOC: ↑ or ↓ methadone Limited data have been reported showing that BOC is safely tolerated with methadone, with no dose reductions required 96% plasma protein bound Metabolized by CYP3A, 2C8 and glucuronidation TPV: No effect on buprenorphine pharmacokinetics BOC Monograph: ↑ or ↓ buprenorphine Clinical monitoring recommended Methadone and buprenorphine: Do not inhibit or induce CYP enzymes Kiser JJ et al. Hepatology 2012;55:1620-1628.

28. 28 TPV + Methadone No dose adjustment required Levin J. 46th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2011), Berlin, Germany, 30 March-3 April 2011

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30. 30 Antidepressants hep-druginteractions.org/

31. 31 Antidepressants BOCTPV Escitalopram CYP2C19 with a minor contribution by CYP3A4 and CYP2D6 ↔ BOC ? ↓ vs ↔ Escitalopram Conflicting reports ↔ TPV ↓ Escitalopram Wide therapeutic index but dose may need to be adjusted Desipramine Trazodone ↑ Desipramine ↑ Trazodone May lead to SEs: nausea, dizziness, hypotension, syncope Use with caution and consider a lower dose Be aware of potential for reductions in SSRI exposures with TPV and BOC, increase the antidepressant doses as needed Kiser JJ et al. Hepatology 2012;55:1620-1628. Levin J. 46th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2011), Berlin, Germany, 30 March-3 April 2011

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33. 33 Anxiolytics and Sleep Aids Flurazepam, triazolam highly dependent on CYP3A for metabolism –Avoid use with BOC and TPV –Consider dose reduction with diazepam Zopiclone: Co administration has not been studied but may increase zopiclone concentrations through CYP3A inhibition. –A clinically significant effect on BOC exposure is unlikely Zolpidem: AUC ↓ 42% by TPV and t1/2 ↓ from 4.32 to 3.37 hrs. Higher dose may be required with TPV Alprazolam (IV) Midazolam (IV) Triazolam (IV) ↑ alprazolam ↑ midazolam ↑ triazolam No interaction studies with IV benzodiazepines Closely monitor for respiratory depression and/or prolonged sedation Avoid use and if necessary consider dose adjustment of benzodiazepines Victrelis Triple monograph. 2011 Merck Canada.Kiser JJ et al. Hepatology 2012;55:1620-1628.

34. 34 Antipsychotics No formal drug interaction studies Predictions must be made based on knowledge of clinical pharmacology of each agent Quetiapine  metabolized solely by CYP3A4 –Avoid with BOC and TPV when possible Aripiprazole  –Reduce by half when TPV or BOC are initiated and titrate antipsychotic dose to effect Risperidone  Co administration has not been studied but may ↑ risperidone concentrations. Kiser JJ et al. Hepatology 2012;55:1620-1628.

35. 35 PIs and Steroids BOC + inhaled budesonide and fluticasone: ↑ budesonide ↑ fluticasone resulting in significantly reduced serum cortisol concentrations Dexamethasone + BOC: ↓ BOC, dexamethasone = CYP3A4/5 inducer May result in loss of therapeutic effect, avoid this combination if possible and use with caution if necessary Victrelis Triple monograph. 2011 Merck Canada.hep-druginteractions.org/ BOC TPV

36. 36 Antimigraine Agents hep-druginteractions.org Ergots: Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Rizatriptan: Co administration has not been studied but, based on metabolism and clearance, a clinically significant interaction is unlikely. Eletriptan: CONTRAINDICATED with TPV due to potential for coronary artery vasospasm, transient MI, MI, ventricular tachycardia, and ventricular fibrillation Victrelis Prescribing Information, Merck & Co Inc, May 2011.

37. 37 Oral Contraceptives BOCTPV Ethinyl estradiol ↓ AUC by ~25↓ AUC by ~25% TPV: ↓ ethinyl estradiol levels  ↑ FSH, LH  ↓ endogenous progesterone levels  loss of contraception efficacy Progesterone component ↑ drosperinone AUC and Cmax by 99% and 57% resp. Progestin only contraception is effective, but it is difficult to know with certainty whether BOC would increase the levels of all progestins or if it is unique to drosperinone May lead to ↑ adverse effects with increased progestin concs. E.g. hyperkalemia ↓ norethindrone slightly (~11%) Kiser JJ et al. Hepatology 2012;55:1620-1628. Do not rely on the use of ethinyl estradiol and progestin-based hormonal contraception during triple therapy for HCV and for 2 weeks after the discontinuation of BOC or TPV BOC + Drospirenone = contraindicated BOC: Alternative methods of non- hormonal contraception are recommended. TPV: Alternative methods of contraception should be used when estrogen-based contraceptives are coadministered with TPV. Tseng A. Toronto General Hospital April 24, 2012

38. 38 Antihypertensive Agents ACEI or Diuretics: CYP enzymes are not involved in the metabolism –Drug interactions unlikely B-Blockers: Only carvedilol metabolized to some extent by CYP3A4 ARBS: Irbesartan and losartan metabolized by CYP3A4 –Dose reductions could be considered Calcium Channel Blockers: Highly reliant on CYP3A –Susceptible to increases in exposure from BOC and TPV –Consider reducing the dose Kiser JJ et al. Hepatology 2012;55:1620-1628.

39. 39 TPV + Amlodipine Lee JF et al. Antimicrob Agents Chemother. 2011 October; 55(10): 4569–4574 Mean plasma concentration-time profile of amlodipine following oral administration with and without telaprevir. Error bars represent the standard error of the mean. Options: Decrease amlodipine dose Use ACE- inhibitor Diuretics

40. 40 Source: Toronto General Hospital. http://www.hivclinic.ca/main/drugs_interact_files/DAA-ARV%20int%20table_summary.pdfhttp://www.hivclinic.ca/main/drugs_interact_files/DAA-ARV%20int%20table_summary.pdf

41. 41 Contraindications to BOC and TPV Antifungals: Use ketoconazole, itraconazole, posaconazole and voriconazole with caution

42. 42 Thank You!

43. 43 Concomitant Drug Effect on Concentration of BOC or Concomitant Drug Clinical Comment Efavirenz↓ BOC ↔ efavirenz ↓ plasma conc. of BOC (Cmin 44% ↓) Clinical outcome has not been directly assessed Tenofovir↔ BOC ↑ Tenofovir ↑ plasma conc. of BOC (Cmax 32% ↑) Changes were not considered clinically significant and no dose adjustment required Ritonavir↓ BOC ↑ or ↓ HIV PIs (Cmax 27% ↓) Changes were not considered clinically significant and no dose adjustment required. Effect of ritonavir-boosted HIV PI on BOC unknown. Effect of BOC on HIV PI concs. is unknown.

44. 44 Immunosuppresants BOC and TPV slow the clearance of cyclosporine and tacrolimus Sirolimus expected to behave similarly to tacrolimus, but has not been studied Cyclosporine may be preferred to tacrolimus in the setting of TPV or BOC based HCV treatment, but it may still be possible to use tacrolimus in a very controlled manner If patient is on cyclosporine, consider empirically reducing cyclosporine dose by 75% empirically Then use TDM to further refine the cyclosporine dose and frequency Another option: Hold doses of cyclosporine and tacrolimus after TPV or BOC have been introduced and redose when concentrations are in desired range