Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy
Volunteers and Patients with Chronic Hepatitis C Virus Infection
Abstract
Aims Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural
protein 5A inhibitor for the treatment of chronic HCV genotype 1
infection. The objective of this analysis was to develop a population
pharmacokinetic model of yimitasvir in Chinese healthy volunteers and
HCV infection patients. Methods The model was performed using data from
219 subjects across 6 studies. Nonlinear mixed effects models were
developed using Phoenix NLME software. The covariates were evaluated
using a stepwise forward inclusion (P < 0.01) and then a
backward exclusion procedure (P < 0.001). Results A
two-compartment model with sequential zero-first order absorption and
first-order elimination reasonably described yimitasvir pharmacokinetics
(PK). The apparent oral clearance and central volume of distribution
were 13.8 l h-1 and 188 l, respectively. The bioavailability (F) of
yimitasvir decreased 12.9% for each 100 mg dose increase. Food was
found to affect absorption rate (Ka) and F. High-fat meal decreased Ka
and F by 90.9% and 38.5%, respectively. Gender and alanine
aminotransferase were identified as significant covariates on apparent
oral clearance. Female subjects had lower clearance than male subjects.
Zero-order absorption duration was longer in healthy volunteers (2.17 h)
than that in patients (1.43 h). Conclusions The population
pharmacokinetic model described yimitasvir PK profile well. Food
decreased Ka and F significantly, so it was recommended to take
yimitasvir at least 2 h before or after a meal. Other significant
covariates were not clinically important.