Clinical evaluation of efficacy, tolerability and pharmacokinetics of yimitasvir phosphate in patients infected with hepatitis C virus

J Pharm Pharmacol. 2018 Jul;70(7):855-864. doi: 10.1111/jphp.12916. Epub 2018 Apr 6.

Abstract

Objective: Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double-blind, placebo-controlled, parallel, multiple-dose study.

Methods: Twenty-four patients with chronic HCV genotype 1 infection were randomized to receive a 7-day course of yimitasvir phosphate at daily doses of 30, 100 or 200 mg or placebo. Antiviral efficacy, resistance profile, pharmacokinetics (PK), safety and tolerability were assessed.

Key findings: The maximal reduction in HCV RNA from baseline was 5.17 log10 IU/ml. However, most patients experienced viral rebound on or before day 3 after yimitasvir treatment was initiated. The PK profile revealed median peak plasma concentrations at 4-12 h postdose and a mean terminal half-life of 14.47-17.09 h, the basis for daily dosing. Steady drug state was achieved following 5 days of daily dosing. The accumulation rate was low (1.29-1.73). There were no significant alterations in vital signs and laboratory findings among all participants.

Conclusions: This study shows that yimitasvir phosphate was well tolerated, and the PK profile supported daily dosing regimens. A 1-week (7-day) treatment course led to a quick and significant reduction in HCV RNA level in this cohort with HCV GT-1 infection.

Keywords: direct-acting antiviral agent; genotype 1; hepatitis C; nonstructural protein 5A; pharmacokinetics.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antiviral Agents / adverse effects
  • Antiviral Agents / blood
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / therapeutic use*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Resistance
  • Female
  • Hepacivirus / drug effects*
  • Hepatitis C / blood
  • Hepatitis C / drug therapy*
  • Hepatitis C / virology
  • Humans
  • Male
  • Middle Aged
  • Organic Chemicals / adverse effects
  • Organic Chemicals / blood
  • Organic Chemicals / pharmacokinetics*
  • Organic Chemicals / therapeutic use*
  • RNA, Viral / genetics
  • Young Adult

Substances

  • Antiviral Agents
  • Organic Chemicals
  • RNA, Viral
  • yimitasvir