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

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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.

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Authors and Affiliations

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

    Erik Mogalian, Diana M. Brainard, Anu Osinusi, Lisa Moorehead, Bernard Murray, Kah Hiing John Ling & Anita Mathias

  2. Elite Research Institute, Miami, FL, USA

    Robert Perry

  3. Compass Research, Orlando, FL, USA

    Craig Curtis

  4. Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA

    Eric Lawitz

  5. Clinical Pharmacology of Miami, Miami, FL, USA

    Kenneth Lasseter

  6. Orlando Clinical Research Center, Orlando, FL, USA

    Thomas Marbury

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  1. Erik Mogalian
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  2. Diana M. Brainard
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  3. Anu Osinusi
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  4. Lisa Moorehead
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  12. Anita Mathias
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Corresponding author

Correspondence to Erik Mogalian.

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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.

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Mogalian, E., Brainard, D.M., Osinusi, A. et al. Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment. Clin Pharmacokinet 57, 1449–1457 (2018). https://doi.org/10.1007/s40262-018-0645-6

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  • DOI: https://doi.org/10.1007/s40262-018-0645-6

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