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Clinical Pharmacokinetics

, Volume 57, Issue 11, pp 1449–1457 | Cite as

Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment

  • Erik Mogalian
  • Diana M. Brainard
  • Anu Osinusi
  • Lisa Moorehead
  • Bernard Murray
  • Kah Hiing John Ling
  • Robert Perry
  • Craig Curtis
  • Eric Lawitz
  • Kenneth Lasseter
  • Thomas Marbury
  • Anita Mathias
Original Research Article

Abstract

Background

The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients.

Methods

In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis].

Results

In the phase I study, plasma exposures (area under the concentration–time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration–time curve over the 24-h dosing interval; AUCtau) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant.

Conclusions

No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.

Notes

Compliance with Ethical Standards

Funding

This study was sponsored by Gilead Sciences, Inc.

Conflict of Interest

Erik Mogalian, Diana M. Brainard, Anu Osinusi, Lisa Moorehead, Bernard Murray, Kah Hiing John Ling, and Anita Mathias are employees of Gilead Sciences, Inc. Robert Perry, Craig Curtis, Eric Lawitz, Kenneth Lasseter, and Thomas Marbury have no conflicts of interest directly relevant to the content of this study.

References

  1. 1.
    Manns MP, Buti M, Gane E, Pawlotsky J, Razavi H, Terrault N, et al. Hepatitis C virus infection. Nat Rev Dis Primers. 2017;3:17006.CrossRefPubMedGoogle Scholar
  2. 2.
    Bhamidimarri KR, Satapathy SK, Martin P. Hepatitis C virus and liver transplantation. Gastroenterol Hepatol. 2017;13:214–20.Google Scholar
  3. 3.
    Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA. Direct acting anti-hepatitis C virus drugs: clinical pharmacology and future direction. J Transl Int Med. 2017;5:8–17.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther. 2016;43:1276–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Davis GL. New approaches and therapeutic modalities for the prevention and treatment of recurrent HCV after liver transplantation. Liver Transpl. 2003;9:S114–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Epclusa®. US FDA packaging information. Foster: Gilead Sciences; 2017.Google Scholar
  7. 7.
    Greig SL. Sofosbuvir/velpatasvir: a review in chronic hepatitis C. Drugs. 2016;76:1567–78.CrossRefPubMedGoogle Scholar
  8. 8.
    European Medicines Agency. 2005. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf. Accessed 30 Sept 2017.
  9. 9.
    Mogalian E, Yang C, Stamm LM, Shen G, Hernandez M, Mathias A. Metabolism and excretion of pangenotypic HCV NS5A inhibitor GS-5816 in humans. In: 16th international workshop on clinical pharmacology of HIV and Hepatitis Therapy, 26–28 May 2015, Washington, DC; 2015: p. 72.Google Scholar
  10. 10.
    Weisberg IS, Jacobson IM. A pangenotypic, single tablet regimen of sofosbuvir/velpatasvir for the treatment of chronic hepatitis C infection. Expert Opin Pharmacother. 2017;18:535–43.CrossRefPubMedGoogle Scholar
  11. 11.
    German P, Mathias A, Brainard D. Kearney BP. Clinical pharmacokinetics and pharmacodynamics of ledipasvir/sofosbuvir, a fixed-dose combination tablet for the treatment of Hepatitis C. Clin Pharmacokinet. 2016;55:1337–51.CrossRefPubMedGoogle Scholar
  12. 12.
    Mogalian E, German P, Kearney BP, Yong Yang C, Brainard D, McNally J, et al. Use of multiple probes to assess transporter- and cytochrome P450-mediated drug–drug interaction potential of the pangenotypic HCV NS5A inhibitor velpatasvir. Clin Pharmacokinet. 2016;55:605–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Wyles DL, Gerber JG. Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction. Clin Infect Dis. 2005;40:174–81.CrossRefPubMedGoogle Scholar
  14. 14.
    Rodighiero V. Effects of liver disease on pharmacokinetics: an update. Clin Pharmacokinet. 1999;37:399–431.CrossRefPubMedGoogle Scholar
  15. 15.
    Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and velpatasvir for HCV in subjects with decompensated cirrhosis. N Engl J Med. 2015;373:2618–28.CrossRefPubMedGoogle Scholar
  16. 16.
    Mogalian E, German P, Kearney BP, Yang CY, Brainard D, Link J, et al. Preclinical pharmacokinetics and first-in-human pharmacokinetics, safety, and tolerability of velpatasvir, a pangenotypic hepatitis C virus NS5A inhibitor, in healthy subjects. Antimicrob Agents Chemother. 2017;61:e02084–020816.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    German P, Moorehead L, Pang P, Vimal M, Mathias A. Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-uninfected female subjects. J Clin Pharmacol. 2014;54:1290–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373:2599–607.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2013 annual data report: liver. Am J Transplant. 2015;15(Suppl. 2):1–28.CrossRefPubMedGoogle Scholar
  20. 20.
    University of Washington. Treatment of hepatitis C in patients with cirrhosis. 2015. http://www.hepatitisc.uw.edu/pdf/special-populations-situations/treatment-cirrhosis/core-concept/all. Accessed 27 Sept 2017.
  21. 21.
    Baumert TF, Jühling F, Ono A, Hoshida Y. Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med. 2017;15:52.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    US and Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. 2015. https://www.fda.gov/Drugs/DrugSafety/ucm468634. Accessed 30 Sept 2017.
  23. 23.
    US and Food and Drug Administration. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. 2016. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM523499.pdf. Accessed 30 Sept 2017.
  24. 24.
    Kirby B, Symonds WT, Kearney BP, Mathias A. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet. 2015;54:677–90.CrossRefPubMedGoogle Scholar
  25. 25.
    Kirby B, Mogalian E, Gao Y, Bhasi K, Mathias, A. Population pharmacokinetic analysis of velpatasvir, a pangenotypic HCV NS5A inhibitor in healthy and hepatitis C virus-infected subjects. In: 17th international workshop on clinical pharmacology of antiviral therapy, 8–10 June 2016, Washington, DC; 2016: p. 27.Google Scholar
  26. 26.
    American Association for the Study of the Human Liver Diseases. HCV guidelines. 2017. http://www.hcvguidelines.org/. Accessed 30 Sept 2017.
  27. 27.
    EASL Clinical Practice Guidelines. 2015. https://www.easl.eu/medias/cpg/HCV-recommendations/English-report.pdf. Accessed 30 Sept 2017.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Erik Mogalian
    • 1
  • Diana M. Brainard
    • 1
  • Anu Osinusi
    • 1
  • Lisa Moorehead
    • 1
  • Bernard Murray
    • 1
  • Kah Hiing John Ling
    • 1
  • Robert Perry
    • 2
  • Craig Curtis
    • 3
  • Eric Lawitz
    • 4
  • Kenneth Lasseter
    • 5
  • Thomas Marbury
    • 6
  • Anita Mathias
    • 1
  1. 1.Gilead Sciences, Inc.Foster CityUSA
  2. 2.Elite Research InstituteMiamiUSA
  3. 3.Compass ResearchOrlandoUSA
  4. 4.Texas Liver InstituteUniversity of Texas Health San AntonioSan AntonioUSA
  5. 5.Clinical Pharmacology of MiamiMiamiUSA
  6. 6.Orlando Clinical Research CenterOrlandoUSA

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