Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment
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The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection.
To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment.
Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study.
Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (C max), respectively. The observed median time to C max was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated.
The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.
We thank all the participants and clinical research unit staff who participated in this study. We also thank Anne Gillespie, Megan Kozisek, Daria Stypinski, John Brejda, Anne Hohnstein, and David Goblot of Celerion for their assistance in this study.
WLM, H-PF, JRB, MI, and WWY conceived and designed the study. KCL, RAP, and TM acquired the data. All of the authors analyzed and interpreted the data. H-PF and XH provided statistical analyses. H-PF and WWY drafted the initial version of this manuscript. All of the authors critically revised the manuscript for important intellectual content and provided approval to submit.
Compliance with Ethical Standards
This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Writing support was provided by Anna Battershill, MSc, and Tim Ibbotson, PhD, of ApotheCom and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Conflict of Interest
WLM and XH were employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at the time the study was conducted. H-PF, LW, GG, FL, DP, LC, CF, JRB, MI, and WWY are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. KCL has been the principal investigator of a study sponsored by Merck. RAP has received research grant support from Merck & Co., Inc. (paid to his institution). TM has received research grant support from Merck & Co., Inc. and owns stock in Orlando Clinical Research Center.
This study was approved by the Chesapeake IRB (institutional review board), Columbia, MD, USA, and the Medical Sciences IRB operated by the Human Subject Research Office at the University of Miami, Miami, FL, USA. The study (MK-8742-009) was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.
Consent to Participate
All participants provided written informed consent prior to participation.
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