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.