Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine

1. Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto Protease Inhibitors in Chronic Hepatitis C:An Update Chapter 2 – Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection November 2012

2. Important Hepatitis C Protease Inhibitor Drug Interactions in Mono andHIV Coinfection Alice Tseng, Pharm.D., FCSHP, AAHIVP Toronto General Hospital University of Toronto

3. Outline Review principles of drug interactions Understand how the pharmacology of DAAs contribute to drug interactions Highlight important HCV drug interactions Outline a strategy for identifying and managing drug interactions Identify pertinent HCV drug interaction resources

4. Drug Interactions Pharmacodynamic Change in pharmacological effect of a drug Additive, synergistic, or antagonistic activity or toxicity e.g., ribavirin + AZT =  anemia Pharmacokinetic Change in the amount of drug(s) in body Absorption, distribution, metabolism, elimination maybe affected Often involves CYP450 system or transporters

5. Interactions Affecting Drug Metabolism Majority of drugs transformed to inactive forms prior to elimination through Phase I (oxidation) or Phase II (conjugation) reactions Phase I primarily involves cytochrome P450 system Superfamily of microsomal heme-containing enzymes Primarily located in liver, small bowel; also kidney, lung, brain CYP3A is the most abundantly expressed isoenzyme, is involved in the metabolism of ~50% of clinically used drugs others: CYP2D6, 2C9, 2B6, 1A2, etc. P-glycoprotein Efflux membrane transporter which prevents drug accumulation in cells; has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure

6. Terms

7. Boceprevir and Telaprevir Pharmacology = +++ potential for interactions with other drugs • can be clinically significant • sometimes unpredictable

8. Potential Consequences of DAA Drug Interactions Interactions may occur in a two-way manner: Concentrations of DAA may be altered by other drug(s) Concentrations of concomitant drug(s) may be altered by DAA Potential consequences include: Increased risk of toxicity Decreased efficacy

9. Statin Interactions Most statins are P450 substrates DAAs can significantly increase statin levels: Atorvastatin: 130%  with boceprevir,7.88-fold  with telaprevir Pravastatin: 60%  with boceprevir  risk of toxicity, including myopathy and rhabdomyolysis [Victrelis & Incivek Product Monographs, 2011. FDA HIV/AIDS Drug Safety Communication, March 1, 2012]

10. Atorvastatin 40 mg + boceprevir: Atorvastatin AUC  130% andCmax  170% vs. atorvastatin alone Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin Atorvastatin 20 mg + telaprevir: Atorvastatin AUC  7.88-fold Combination is contraindicated Atorvastatin Interactions with Boceprevir and Telaprevir 30,000 100 25,000 Atorvastatin alone Atorvastatin + Boceprevir 10.0 20,000 With telaprevir 1.00 Concentration (ng/mL) Atorvastatin concentration (pg/mL) 15,000 Without telaprevir 10,000 0.10 5,000 0 0.01 0 8 16 24 32 40 48 0 10 20 30 40 50 Time (hrs) Nominal time (hrs) Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122 Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

11. Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg Calcium channel blockers (CCBs) Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates Concentrations may be  by boceprevir or telaprevir Use with caution, clinical monitoring Consider dose reduction 5.00 With telaprevir 0.50 Concentration (ng/mL) Without telaprevir 0.05 0.01 0 50 100 150 200 250 Nominal time (hrs) • Amlodipine AUC  179% • Monitor for dose-related toxicity Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

12. Antihypertensive Medications

13. Treatment of Depression in HCV

14. Methadone Interactions • Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A,85% protein bound; R-isomer is biologically active enantiomer • Boceprevir interaction: • In the presence of steady-state boceprevir, R-methadone AUC  16%, Cmax  10%; no clinical effects noted including opioid withdrawal • Boceprevir exposures not affected by methadone • Telaprevir interaction: • In the presence of steady-state telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%, but median unbound Cmin ofR-methadone was similar before and during telaprevir coadministration and no withdrawal symptoms were noted • A priori methadone dose adjustments are not required when initiating DAA therapy, but close monitoring is recommended, with methadone dose adjustments if necessary Hulskotte et al. 2012, Van Heeswijk et al. 2011.

15. Hormonal Contraceptives with DAAs Hormonal contraceptives may not be as effective in women taking boceprevir or telaprevir Boceprevir (Victrelis): 99%  AUC drospirenone, 24%  AUC EE Use 2 alternate effective methods of contraception during treatment with BOC and Peg IFN/RBV Drospirenone (Yaz®, Yasmin®, Angelique®) is contraindicated Telaprevir (Incivek): 28%  AUC, 33%  Cmin of EE Use 2 additional non-hormonal methods of effective birth control during TVR dosing and for 2 months after the last intake of TVR.

16. Benzodiazepine Interactions Majority are substrates of CYP3A4 Risk for prolonged/excessive sedation Oral midazolam & triazolam are contraindicated with boceprevir and telaprevir IV midazolam: consider  dose, close monitoring for respiratory depression or prolonged sedation Other benzodiazepines:  dose and monitor Consider using benzodiazepines that are glucuronidated: Lorazepam, oxazepam, temazepam

17. Inhaled Corticosteroids Corticosteroids are CYP3A4 substrates Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations Inhaled/nasal fluticasone, budesonide: Avoid co-administration with HCV PIs if possible, particularly for extended durations. May wish to use corticosteroid associated with less adrenal suppression (e.g., beclomethasone, ciclesonide) Use lowest possible dose, consider non-steroidal options Victrelis & Incivek. Product Monographs, 2011

18. PDE5 Inhibitors (sildenafil, tadalafil, vardenafil) PDE5 inhibitors are substrates of CYP3A4 Potential for DAAs to  concentrations Dose-related side effects (headache, vasodilation, dyspepsia, visual disturbances) Contraindicated with DAAs if using for PAH For erectile dysfunction, use a lower dose with DAAs: Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h Do not use vardenafil

19. Interactions Between HCV & HIV Medications Challenges in treating HIV/HCV co-infected patients Additive toxicities: Anemia: ribavirin, zidovudine, DAAs CNS: interferon, efavirenz Potential for negative 2-way interactions  concentrations of HIV agents  concentrations of HCV DAAs

20. Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir

21. Managing Drug Interactions:1) Medication Reconciliation Ensure medication records are up to date at each visit Prescription, OTC, vitamins/herbals, recreational drugs, inhalers, topical, prn agents Confirm doses, prn drugs Include all agents that have been started or stopped Patient education: Encourage patients to ask before taking any new prescription/non-prescription drug or supplement Communication with other HCP!

22. Managing Drug Interactions: 2) Identify Potential Interactions Use a systematic approach to identify combinations of potential concern Apply knowledge of known PK characteristics Overlapping CYP pathways, substrate, inducer, inhibitor High index of suspicion with key classes of drugs Utilize current drug information resources: Product monographs, CPS, literature Conference abstracts, specialized HCV drug interaction websites

23. Drugs Contraindicated with Boceprevir and Telaprevir (1) Victrelis & Incivek. Product Monographs, 2011

24. Drugs Contraindicated with Boceprevir and Telaprevir (2) Victrelis & Incivek. Product Monographs, 2011

25. Managing Drug Interactions:Therapeutic Options Determine clinical significance Evaluate therapeutic options: Alter drug dose/dosing frequency Substitute with alternate agent Can any drugs be permanently or temporarily discontinued while on DAA treatment? Consider patient convenience and cost factors Patient counselling & close monitoring is critical

26. Summary High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes Consequences may include therapeutic failure and increased toxicity Often, interactions can be managed, but heightened level of awareness is needed Use a systematic approach to identify and manage individual drug regimens Importance of a specialized, inter-disciplinary team including pharmacy

27. General Hansten PD. Science Med 1998;16-25. Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases, 2nd edition, c. 2005, pp:13-39. Metheny CJ et al. Pharmacotherapy 2001;21:778-96. Interactions in HCV and HIV: Kiser J et al. Hepatology 2012;55:1620-8. Tseng & Foisy. Curr Infect Dis Rep 2012;14:67-82. Internet Toronto General Hospital Immunodeficiency Clinic; www.hivclinic.ca Liverpool Pharmacology Group; www.hep-druginteractions.org www.hcvdruginfo.ca Additional Resources

28. The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease. For more information visit www.liver.ca or call 1-800-563-5483. This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc. The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians.