Introduction
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) [1]. In 2002, National Institutes of Health Consensus Development Conference Statement reported more than 184 million persons had HCV infection [2]. An epidemiology in 2015 estimated that 1.0% of the world population corresponding to approximate 71 million people were active cases [3]. Every year three to four million people are newly infected and approximately 350,000 deaths occur [4]. HCV demonstrates great genetic diversity with 7 genotypes and at least 67 subtypes [1]. Overall, genotype 1 dominates with 44% of infections, followed by genotype 3 (25%) and 4 (15%) [3]. In China, it is estimated that at least 25 million individuals infected with HCV [5] and genotype 1b is the most common type (56.8%), followed by genotype 2 (24.1%) and 3 (9.1%) [6].
Yimitasvir is a novel, oral HCV non-structural protein 5A (NS5A) inhibitor for the treatment of chronic HCV genotype 1 infection in combination with sofosbuvir. The chemical structure of yimitasvir is shown in Figure 1. The pharmacokinetic profile of yimitasvir has been evaluated in healthy volunteers and patients with chronic HCV infection [7, 8]. Following fasted single oral dose of yimitasvir in healthy volunteers, yimitasvir was absorbed with a peak concentration (Cmax) 3.5-4.0 h post-dose. Area under the concentration-time curve (AUC) and Cmax increased in a dose-proportional manner from 30 to 100 mg but a less than proportional manner from 100 to 600 mg (single ascending dose [SAD] study) [7]. Similarly, less than dose-proportional manner was found in multiple ascending dose (MAD) study in the range of 100-400 mg once daily for 7 consecutive days. However, the result from phase 1b study in patient population showed that yimitasvir exhibited near dose-proportional increase in exposure from 30 to 200 mg administered during the night (4 h after dinner) [8]. Yimitasvir was approximately 79.2-86.6% bound to human plasma proteins and the binding was independent of drug concentration over the range of 100-2000 ng ml-1. No metabolism of yimitasvir was detected in vitro during incubations with hepatic microsomes from mice, rats, dogs, monkeys and humans. Less than 0.04% of yimitasvir was recovered in urine as the parent drug through 7 days post-dose and fecal excretion of parent drug was the major route of elimination [7]. The terminal half-life (t1/2) of yimitasvir was 13.4-19.7 h, supporting once daily dosing schedule. Steady state was achieved by day 5 following the once daily dosing regimen. The accumulation ratio was 1.32-1.34, consistent with half-life. A high-fat meal reduced absorption rate with Tmax occurring at 5-12 h post-dose and resulted in approximate 50% and 63% decrease in yimitasvir AUC and Cmax, respectively [7]. Yimitasvir is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Yimitasvir is a weak inhibitor of cytochrome P450 (CYP) 2C8, but does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. Yimitasvir may be a weak inducer of CYP3A4.
In phase 2 study, yimitasvir 100 or 200 mg was administered once daily for 12 weeks in combination with 400 mg sofosbuvir in patients with chronic HCV infection. Similar to other HCV NS5A inhibitors such as velpatasvir [9] and ledipasvir [10], yimitasvir PK profile was not affected by co-medication of sofosbuvir. The primary endpoint of phase 2 study was sustained virologic response (HCV RNA less than lower limit of quantification [LLOQ]) 12 (SVR12) weeks after the completion of treatment. SVR12 rates were achieved 100% in both 100 mg yimitasvir/400 mg sofobuvir and 200 mg yimitasvir/400 mg sofobuvir groups. The adverse reaction rates were comparable between 100 mg (35.9%) and 200 mg (36.9%) groups. The most common adverse reactions were neutropenia (3.9%), leukopenia (3.1%), hypercholesterolemia (3.1%) and fatigue (3.1%). All of these adverse reactions were grade 1 or 2 in severity. In summary, no dose-response relationship for efficacy and safety was observed in phase 2 study.
The aim of our study was to develop a population PK model to characterize yimitasvir PK in Chinese population and to identify the significant covariates affecting yimitasvir PK. This model will be further updated with much more patient PK data from phase 3 study and be used for predicting individual subject exposure for efficacy and safety exposure-response analysis of yimitasvir.