Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment
- 255 Downloads
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.
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].
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.
No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.
Compliance with Ethical Standards
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.
- 2.Bhamidimarri KR, Satapathy SK, Martin P. Hepatitis C virus and liver transplantation. Gastroenterol Hepatol. 2017;13:214–20.Google Scholar
- 6.Epclusa®. US FDA packaging information. Foster: Gilead Sciences; 2017.Google Scholar
- 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.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
- 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.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
- 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.
- 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.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.
- 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.American Association for the Study of the Human Liver Diseases. HCV guidelines. 2017. http://www.hcvguidelines.org/. Accessed 30 Sept 2017.
- 27.EASL Clinical Practice Guidelines. 2015. https://www.easl.eu/medias/cpg/HCV-recommendations/English-report.pdf. Accessed 30 Sept 2017.