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Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

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Abstract

Sofosbuvir (SOVALDI®), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS-331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90 % of systemic drug-related material exposure, and provided comparable exposure–response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration–time curve (AUC) and higher sofosbuvir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV-infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV-infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure–response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic–pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients.

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References

  1. SOVALDI® (sofosbuvir) tablets, for oral use. US prescribing information [revised]. Foster City: Gilead Sciences, Inc.; 2014.

  2. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US prescribing information. Foster City: Gilead Sciences, Inc.; 2014.

  3. Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010;285(45):34337–47. doi:10.1074/jbc.M110.161802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  5. Babusis D, Curry MP, Denning J, Wang T, Kirby B, Murakami E, et al. Translational studies to understand the mechanism of liver delivery by sofosbuvir [oral presentation]. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 19–21 May 2014; Washington, DC.

  6. Babusis D, Curry MP, Denning J, Park Y, Murakami E, Afdhal N, et al. Nucleotide analog levels in liver explants from HCV infected subjects undergoing liver transplantation after up to 24 weeks sofosbuvir (GS-7977) with ribavirin treatment [poster no. 1,091]. 64th Annual Meeting of the American Association for the Study of Liver Diseases; 1–5 Nov 2013; Washington, DC.

  7. SOVALDI® (sofosbuvir) tablets, for oral use. EMA summary of product characteristics [revised]. Foster City: Gilead Sciences, Inc.; 2014.

  8. Cornpropst M, Denning J, Clemons D, Marbury T, Alcorn H, Smith W, et al. The effect of renal impairment and end stage renal disease on the single-dose pharmacokinetics of GS-7977 [poster no. 1,101]. 47th Annual Meeting of the European Association for the Study of the Liver; 18–22 Apr 2012; Barcelona.

  9. Rodriguez-Torres M, Lawitz E, Kowdley KV, Nelson DR, Dejesus E, McHutchison JG, et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol. 2013;58(4):663–8. doi:10.1016/j.jhep.2012.11.018.

    Article  CAS  PubMed  Google Scholar 

  10. Kirby B, Gordi T, Symonds WT, Kearney BP, Mathias A. Population pharmacokinetics of sofosbuvir and its major metabolite (GS-331007) in healthy and HCV-infected adult subjects [poster no. 1,106]. 64th Annual Meeting of the American Association for the Study of Liver Diseases; 1–5 Nov 2013; Washington, DC.

  11. Lawitz E, Rodriguez-Torres M, Denning JM, Albanis E, Cornpropst M, Berrey MM, et al. Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection. Antimicrob Agents Chemother. 2013;57(3):1209–17. doi:10.1128/AAC.01263-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–87. doi:10.1056/NEJMoa1214853.

    Article  CAS  PubMed  Google Scholar 

  13. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867–77. doi:10.1056/NEJMoa1214854.

    Article  CAS  PubMed  Google Scholar 

  14. Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993–2001. doi:10.1056/NEJMoa1316145.

    Article  PubMed  Google Scholar 

  15. Lawitz E, Rodriguez-Torres M, Cornpropst M, Denning J, Clemons D, McNair L, et al. The effect of hepatic impairment on the safety, pharmacokinetics, and antiviral activity of GS-7977 in hepatitis C infected subjects treated for seven days [poster no. 1,130]. 47th Annual Meeting of the European Association for the Study of the Liver; 18–22 Apr 2012; Barcelona.

  16. Gane E, Robson RA, Bonacini M, Maliakkal B, Kirby B, Liu L, et al. Safety, antiviral efficacy, and pharmacokinetics of sofosbuvir in patients with severe renal impairment [abstract no. 966]. 65th Annual Meeting of the American Association for the Study of Liver Diseases; 7–11 Nov 2014; Boston.

  17. Mathias A, Cornpropst M, Clemens D, Denning J, Symonds WT. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants cyclosporine A or tacrolimus in healthy volunteers [poster no. 1,869]. 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 9–13 Nov 2012; Boston.

  18. Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology. 2015;148(1):108–17. doi:10.1053/j.gastro.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  19. Soriano V, Vispo E, Labarga P, Medrano J, Barreiro P. Viral hepatitis and HIV co-infection. Antiviral Res. 2010;85(1):303–15. doi:10.1016/j.antiviral.2009.10.021.

    Article  CAS  PubMed  Google Scholar 

  20. Limketkai BN, Mehta SH, Sutcliffe CG, Higgins YM, Torbenson MS, Brinkley SC, et al. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA. 2012;308(4):370–8. doi:10.1001/jama.2012.7844.

    Article  CAS  PubMed  Google Scholar 

  21. Kirby B, Mathias A, Rossi S, Moyer C, Shen G, Kearney BP. No Clinically significant pharmacokinetic interactions between sofosbuvir (GS-7977) and HIV antiretrovirals atripla, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers [poster no. 1,877]. 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 9–13 Nov 2012; Boston.

  22. Sulkowski MS, Naggie S, Lalezari J, Fessel WJ, Mounzer K, Shuhart M, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA. 2014;312(4):353–61. doi:10.1001/jama.2014.7734.

    Article  PubMed  Google Scholar 

  23. ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets. US prescribing information. Foster City: Gilead Sciences and Bristol-Myers Squibb, LLC; 2012.

  24. Mouly S, Lown KS, Kornhauser D, Joseph JL, Fiske WD, Benedek IH, et al. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther. 2002;72(1):1–9. doi:10.1067/mcp.2002.124519.

    Article  CAS  PubMed  Google Scholar 

  25. Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, et al. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother. 2007;51(10):3498–504. doi:10.1128/AAC.00671-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr. 2010;55(3):323–9. doi:10.1097/QAI.0b013e3181eb376b.

    Article  CAS  PubMed  Google Scholar 

  27. EDURANT® (rilpivirine) tablets. US prescribing information. Raritan: Tibotec Pharmaceuticals; 2011.

  28. ISENTRESS® (raltegravir) film-coated tablets, for oral use, ISENTRESS® (raltegravir) chewable tablets, for oral use. US prescribing information [revised]. Whitehouse Station: Merck & Co., Inc.; 2012.

  29. Hanley WD, Wenning LA, Moreau A, Kost JT, Mangin E, Shamp T, et al. Effect of tipranavir–ritonavir on pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2009;53(7):2752–5. doi:10.1128/AAC.01486-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008;52(12):4338–43. doi:10.1128/AAC.01543-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Martinez AD, Dimova R, Marks KM, Beeder AB, Zeremski M, Kreek MJ, et al. Integrated internist—addiction medicine—hepatology model for hepatitis C management for individuals on methadone maintenance. J Viral Hepat. 2012;19(1):47–54. doi:10.1111/j.1365-2893.2010.01411.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther. 2001;70(1):48–57. doi:10.1067/mcp.2001.116793.

    Article  CAS  PubMed  Google Scholar 

  33. Eap CB, Bertschy G, Powell K, Baumann P. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone. J Clin Psychopharmacol. 1997;17(2):113–7.

    Article  CAS  PubMed  Google Scholar 

  34. Eap CB, Cuendet C, Baumann P. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein. Clin Pharmacol Ther. 1990;47(3):338–46.

    Article  CAS  PubMed  Google Scholar 

  35. Denning J, Cornpropst M, Clemons D, Fang L, Sale M, Berrey M, et al. Lack of effect of the nucleotide analog polymerase inhibitor PSI-7977 on methadone pharmacokinetics and pharmacodynamics [abstract no. 372]. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 4–8 Nov 2011; San Francisco.

  36. German P, Moorehead L, Pang PS, Vimal M, Mathias A. Lack of a clinically important pharmacokinetic interaction between norgestimate/ethinyl estradiol and sofosbuvir (SOF) or ledipasvir (LDV) in HCV-uninfected female subjects [poster no. 469]. 64th Annual Meeting of the American Association for the Study of Liver Diseases; 1–5 Nov 2011; Washington, DC.

  37. ORTHO TRI-CYCLEN® Lo Tablets (norgestimate/ethinyl estradiol). US prescribing information [revised]. Manati: Janssen Ortho, LLC.; 2012.

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Acknowledgments

On 17 January 2012, Gilead Sciences Inc. (Gilead, Foster City, CA, USA) completed its acquisition of Pharmasset, Inc., making it a wholly owned subsidiary of Gilead. Therefore, all clinical study responsibilities were transferred to Gilead. PSI-7977 and its metabolites PSI-352707, PSI-7409, and PSI-6206 were assigned the Gilead Identification numbers GS-7977, GS-566500, GS-461203, and GS-331007, respectively. Sofosbuvir is the generic name for GS-7977. All authors are employees of Gilead, contributed significantly to the design, conduct, analyses and interpretation of data, and were involved in the preparation, review, and approval of this article. Gilead Sciences, Inc. provided funding for the research presented in this article. Sofosbuvir project team and individual study team members contributed towards the conduct and management of clinical trials described here. All authors are stockholders of Gilead Sciences, Inc.

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Authors and Affiliations

  1. Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA

    Brian J. Kirby, William T. Symonds, Brian P. Kearney & Anita A. Mathias

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  1. Brian J. Kirby
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Correspondence to Anita A. Mathias.

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Kirby, B.J., Symonds, W.T., Kearney, B.P. et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin Pharmacokinet 54, 677–690 (2015). https://doi.org/10.1007/s40262-015-0261-7

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