Abstract
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. The model was performed using data from 219 subjects across six 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). 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). 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.
Highlights
Chronic infection with hepatitis C virus (HCV) is a public health concern in the world, which can lead to liver cirrhosis, and/or hepatocellular carcinoma (Jafri and Gordan, 2018)
A total of 3,540 pharmacokinetic records (99.1%) from 219 subjects (72 healthy volunteers and 147 HCV infection patients) were included for model development. 31 (0.9%) samples below lower limit of quantification (LLOQ) were excluded from analysis
There was no difference in exposures between patients and healthy volunteers. This population PK analysis was established using rich and sparse PK samples collected from six clinical trials including 72 healthy volunteers and 147 HCV infection patients
Summary
Chronic infection with hepatitis C virus (HCV) is a public health concern in the world, which can lead to liver cirrhosis, and/or hepatocellular carcinoma (primary liver cancer) (Jafri and Gordan, 2018). An epidemiology in 2015 estimated that 1.0% of the world population corresponding to approximate 71 million people were active cases Genotype 1 dominates with 44% of infections, followed by genotype 3 (25%) and 4 (15%) (Polaris Observatory HCV Collaborators, 2017). In China, it is estimated that at least 25 million individuals infected with HCV (Bian et al, 2017) and genotype 1b is the most common type (56.8%), followed by genotype 2 (24.1%) and 3 (9.1%) (Chinese Society of Hepatology and Chinese Society of Infectious Diseases, 2015)
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