The Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor [PublishAheadOfPrint]

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic hepatitis C virus (HCV) genotype 1 or 4 infection. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR 200, 100, and 50 mg in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, versus healthy matched controls (Protocol MK-5172_p013). Participants with mild, moderate, or severe HI and race-, age-, sex-, and body mass index--matched controls (aged 18-65 years) were enrolled in a 3-part, open-label, sequential-panel, pharmacokinetic study. Participants received multiple oral doses of 200 (2x100-mg tablets), 100 (1x100-mg tablet), or 50 mg (2x25-mg tablets) GZR once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls per hepatic cohort. Participants with HI demonstrated higher GZR exposure compared with healthy matched controls, and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC_0-24 in participants with mild, moderate, or severe HI was 2-, 5-, and 12-fold higher, respectively, than healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated in those with moderate or severe HI (Child-Pugh B or C), as they may have significantly increased GZR exposures that may lead to increased risk of transaminase elevations.

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