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Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

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Abstract

Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2–4 h and an elimination half-life (t ½) of ≈15–20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4–mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion–transporting polypeptide (OATP)–mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug–drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

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References

  1. Gower E, Estes CC, Hindman S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61(S1):S45–57.

    Article  PubMed  Google Scholar 

  2. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–42.

    Article  PubMed  Google Scholar 

  3. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513–21 (521.e1-6).

    Article  PubMed  Google Scholar 

  4. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–206.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.

    Article  CAS  PubMed  Google Scholar 

  6. Vertex Pharmaceuticals Incorporated. Incivek™ (telaprevir) film coated tablets: prescribing information. US Food and Drug Administration. 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201917lbl.pdf. Accessed 22 Jun 2015.

  7. Schering Corporation. Victrelis™ (boceprevir) capsules: prescribing information. US Food and Drug Administration. May 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf. Accessed 22 Jun 2015.

  8. Gogela NA, Lin MV, Wisocky JL, Chung RT. Enhancing our understanding of current therapies for hepatitis C virus (HCV). Curr HIV/AIDS Rep. 2015;12:68–78.

    Article  PubMed  Google Scholar 

  9. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2014. J Hepatol. 2014;60:392–420.

    Article  Google Scholar 

  10. McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, et al. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012;56:5387–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Manns M, Pol S, Jacobson IM, Marcellin P, Gordon SC, Peng CY, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. 2014;384:414–29.

    Article  CAS  PubMed  Google Scholar 

  12. Bronowicki JP, Ratziu V, Gadano A, Thuluvath PJ, Bessone F, Martorell CT, et al. Randomized trial of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 or 4 chronic hepatitis C. J Hepatol. 2014;61:1220–7.

    Article  CAS  PubMed  Google Scholar 

  13. Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146:420–9.

    Article  CAS  PubMed  Google Scholar 

  14. Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, et al. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014;57:1730–52.

    Article  CAS  PubMed  Google Scholar 

  15. Mosure KW, Knipe JO, Browning M, Arora V, Shu Y-Z, Thomas P, et al. Preclinical pharmacokinetics and in vitro metabolism of asunaprevir: a potent HCV NS3 protease inhibitor. J Pharm Sci. 2015;. doi:10.1002/jps.24356.

    PubMed  Google Scholar 

  16. Eley T, Han YH, Huang S, He B, Li W, Bedford W, et al. Organic anion–transporting polypeptide-mediated transport of, and inhibition by, asunaprevir, an inhibitor of hepatitis C virus NS3 protease. Clin Pharm Ther. 2015;97:159–66.

    Article  CAS  Google Scholar 

  17. Eley T, He B, Huang S, Li W, Pasquinelli C, Rodrigues AD, et al. Pharmacokinetics of the NS3 protease inhibitor, asunaprevir (ASV, BMS-650032), in phase I studies in subjects with or without chronic hepatitis C. Clin Pharmacol Drug Dev. 2013;2(4):316–27.

    Article  CAS  Google Scholar 

  18. Pasquinelli C, McPhee F, Eley T, Villegas C, Sandy K, Wendelburg P, et al. Single and multiple ascending dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C. Antimicrob Agents Chemother. 2012;56:1838–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Shiozaki T, Ueno T, Nagashima H, Yamahira N, Hiraoka M, Eley T, et al. Single and multiple-ascending dose studies to evaluate the safety, tolerability and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects. Int J Clin Pharmacol Ther. 2015;53(4):292–302.

    CAS  PubMed  Google Scholar 

  20. Eley T, Sevinsky H, Huang SP, He B, Zhu K, Kandoussi H, et al. The pharmacokinetics of daclatasvir and asunaprevir administered in combination in studies in healthy subjects and patients infected with hepatitis C virus. Clin Drug Investig. 2014;34:661–71.

    Article  CAS  PubMed  Google Scholar 

  21. Eley T, Colston E, Li J, Garimella T, He B, Dutta A, et al. Asunaprevir does not have an effect on QTcF interval in healthy subjects [poster no. P_53]. In: 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC; 19–21 May 2014.

  22. Eley T, Chan P, Sverdlov O, He B, Bedford B, Kandoussi H, et al. Improved bioavailability and mitigated food effect for asunaprevir utilizing a lipid-based formulation: similar exposure with 100 mg twice-daily soft-gel capsule relative to 200 mg twice daily of phase 2 tablet [abstract/poster no. A-1247]. In: 52nd Interscience Conference Antimicrobial Agents Chemotherapy. San Francisco; 9–12 Sep 2012.

  23. Eley T, Gardiner D, Persson A, He B, You X, Shah V, et al. Evaluation of drug interaction potential of the HCV protease inhibitor asunaprevir (ASV; BMS-650032) at 200 mg twice daily in metabolic cocktail and P-glycoprotein (P-gp) probe studies in healthy volunteers [abstract]. Hepatology. 2011;54:abstract no. 381.

  24. Morcos PN, Moreira SA, Brennan BJ, Blotner S, Shulman NS, Smith PF. Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate. Eur J Clin Pharmacol. 2013;69:1777–84.

    Article  CAS  PubMed  Google Scholar 

  25. Eley T, Chan P, Huang S, Wind-Rotolo M, Delmonte T, He B, et al. Asunaprevir in Japanese subjects in phase 2: exposure-safety versus US/EU-based subjects and preliminary assessment of correlation with single nucleotide polymorphisms (SNPs) in liver uptake transporters. Hepatology. 2012;56(Suppl 1):1070A–1A.

    Google Scholar 

  26. Garimella T, Li W, Wind-Rotolo M, He B, Zhu L, Chan P, et al. Assessment of correlation of asunaprevir with polymorphisms in liver uptake transporters (OATP1B1 and 2B1): results of an integrated population PK analyses [poster no. pp-32]. In: 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC; 19–21 May 2014.

  27. Zhu L, Li H, Chan P, Eley T, Bifano M, Osawa M, et al. Population pharmacokinetic analysis of asunaprevir in subjects with hepatitis C virus (HCV) infection [poster no. T-001]. American Conference on Pharmacometrics (ACoP) Meeting. Las Vegas; 12–15 Oct 2014.

  28. Kikuchi R, McCown M, Olson P, Tateno C, Morikawa Y, Katoh Y, et al. Effect of hepatitis C virus infection on the mRNA expression of drug transporters and cytochrome p450 enzymes in chimeric mice with humanized liver. Drug Metab Dispos. 2010;38:1954–61.

    Article  PubMed  Google Scholar 

  29. Nakai K, Tanaka H, Hanada K, Ogata H, Suzuki F, Kumada H, et al. Decreased expression of cytochromes P450 1A2, 2E1, and 3A4 and drug transporters Na+-taurocholate-cotransporting polypeptide, organic cation transporter 1, and organic anion–transporting peptide-C correlates with the progression of liver fibrosis in chronic hepatitis C patients. Drug Metab Dispos. 2008;36:1786–93.

    Article  CAS  PubMed  Google Scholar 

  30. Edginton AN, Willmann S. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet. 2008;47:743–52.

    Article  PubMed  Google Scholar 

  31. Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 2010;49:189–206.

    Article  CAS  PubMed  Google Scholar 

  32. Eley T, He B, Chang I, Colston E, Child M, Bedford W, et al. The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor. Antivir Ther. 2015;20(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  33. Garimella T, He B, Luo W, Colston E, Zhu K, Kandoussi H, et al. Asunaprevir pharmacokinetics and safety in subjects with impaired renal function. Hepatology. 2013;58:430A.

    Google Scholar 

  34. Bronowicki JP, Pol S, Thuluvath PJ, Larrey D, Martorell CT, Rustgi VK, et al. Randomized study of asunaprevir plus pegylated interferon-alpha and ribavirin for previously untreated genotype 1 chronic hepatitis C. Antivir Ther. 2013;18:885–93.

    Article  CAS  PubMed  Google Scholar 

  35. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216–24.

    Article  CAS  PubMed  Google Scholar 

  36. Lok AS, Gardiner DF, Hezode C, Lawitz EJ, Bourliere M, Everson GT, et al. Randomized trial of daclatasvir and asunaprevir with or without pegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol. 2014;60:490–9.

    Article  CAS  PubMed  Google Scholar 

  37. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59:2083–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Chan P, Zhu L, Eley T, Bifano M, Hughes E, Bertz R. Exposure-safety analysis for asunaprevir and daclatasvir in dual combination in subjects with hepatitis C virus infection. J Pharmacokinet Pharmacodyn. 2014;41:S7.

    Article  Google Scholar 

  39. Wang X, Li W, Huang S, He B, Chung E, Griffies A, et al. Evaluation of pharmacokinetic drug–drug interaction (DDI) between BMS-791325, an NS5B non-nucleoside polymerase inhibitor, daclatasvir and asunaprevir in triple combination in HCV genotype 1-infected patients [abstract]. J Hepatol. 2013;58(Suppl 1):S184.

    Article  Google Scholar 

  40. Poordad F, Sievert W, Mollison L, Brau N, Levin J, Sepe T, et al. All-oral fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325 for non-cirrhotic patients with HCV genotype 1 infection: UNITY-1 phase 3 SVR12 results. Hepatology. 2014;60:1271A–2A.

    Google Scholar 

  41. Muir A, Poordad F, Lalezari JP, Everson GT, Dore GJ, Kwo P, et al. All-oral fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325, ±ribavirin, for patients with chronic HCV genotype 1 infection and compensated cirrhosis: UNITY-2 phase 3 SVR12. Hepatology. 2014;60:1267A–8A.

    Article  Google Scholar 

  42. Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27:55–67.

    Article  CAS  PubMed  Google Scholar 

  43. Garimella T, Adamczyk R, Hu P, Stonier M, Kandoussi H, Colston E, et al. No clinically-relevant interactions between asunaprevir and selective serotonin reuptake inhibitors (escitalopram and sertraline) in healthy subjects. Hepatology. 2013;58(4 Suppl):445A.

    Google Scholar 

  44. Garimella T, Eley T, He B, Luo W, Crowell J, Kandoussi H, et al. Evaluation of drug–drug interactions between asunaprevir and methadone or buprenorphine/naloxone [poster no. 823]. IDWeek 2014. Philadelphia; 8–12 Oct 2014.

  45. Eley T, He B, Huang S, Stonier M, Bedford W, Kandoussi H, et al. Effect of multiple-dose ketoconazole and the effect of multiple-dose rifampin on the pharmacokinetics (PK) of the NS3 protease inhibitor asunaprevir. Reviews in Antiviral Therapy and Infectious Diseases. 2013;6:15.

  46. Shitara Y, Takeuchi K, Nagamatsu Y, Wada S, Sugiyama Y, Horie T. Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake. Drug Metab Pharmacokinet. 2012;27:368–78.

    Article  CAS  PubMed  Google Scholar 

  47. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–81.

    Article  CAS  PubMed  Google Scholar 

  48. Suzuki Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Chayama K, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58:655–62.

    Article  CAS  PubMed  Google Scholar 

  49. Hassanein T, Sims K, Bennett M, Gitlin N, Lawitz E, Nguyen T, et al. All-oral therapy with daclatasvir in combination with asunaprevir and BMS-791325 in treatment-naive patients with chronic HCV genotype 4 infection [abstract no. 1163]. J Hepatol. 2014;60(Suppl 1):S472.

  50. Jensen D, Sherman K, Hézode C, Pol S, Zeuzem S, De Ledinghen V, et al. Daclatasvir and asunaprevir plus peginterferon alfa-2a and ribavirin in patients with HCV genotype 1 or 4 infection: phase 3 HALLMARK-QUAD results [poster no. 821]. ID Week 2014. Philadelphia; 8–12 Oct 2014.

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Acknowledgments

The authors would like to thank Bing He for assistance with pharmacokinetic analyses and Fiona McPhee for providing mechanism of action and replicon antiviral activity data. Editorial assistance was provided by Andrew Stead of Articulate Science Ltd and funded by Bristol-Myers Squibb.

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  1. Research and Development, Bristol-Myers Squibb, P O Box 4000, Princeton, NJ, 08543-4000, USA

    Timothy Eley, Tushar Garimella, Wenying Li & Richard J. Bertz

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  1. Timothy Eley
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Correspondence to Timothy Eley.

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Timothy Eley, Tushar Garimella, Wenying Li and Richard J. Bertz are employees and stock holders of Bristol-Myers Squibb.

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Eley, T., Garimella, T., Li, W. et al. Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions. Clin Pharmacokinet 54, 1205–1222 (2015). https://doi.org/10.1007/s40262-015-0299-6

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