Discussion
This population PK analysis was established using rich and sparse PK samples collected from 6 clinical trials including 72 healthy volunteers and 147 HCV infection patients. A two-compartment model with a sequential zero-first order absorption and first-order elimination could described the PK profiles of yimitasvir well. After a stepwise forward inclusion and backward exclusion covariate screen procedure, statistically significant covariates in the final model were food status on Ka and F, gender and ALT on CL/F, and disease status on Td.
Results from phase 1 SAD study in healthy volunteers suggested that the exposure (AUC and Cmax) of yimitasvir increased less than proportionally in the range of 30-600 mg. Similar exposures were found between 400 mg and 600 mg groups indicating a limited absorption. Less than dose proportionality was also observed in phase 2 study in patients after oral administrations of 100 or 200 mg yimitasvir in combination with 400 mg sofosbuvir. Sofosbuvir did not affect the pharmacokinetic properties of yimitasvir, which had been proven by other drugs targeting HCV NS5A protein like velpatasvir [9] and ledipasvir [10]. However, the exposure of yimitasvir was dose-proportional in phase 1b trial in patients with chronic HCV genotype 1 infection after single and multiple oral dosing from 30 to 200 mg. The mechanism behind the difference in the PK linearity of yimitasvir between phase 1b and the other trials is unclear. One significant difference in clinical trial design was that subjects in phase 1b trial administered yimitasvir in the evening after dinner for more than 4 h, while subjects in other trials took the drug in the morning under fasted state. The inefficiency of gastric emptying resulted in decrease of absorption rate with a median time to peak concentration (Tmax) of 4-12 h and a 40% AUC decrease when compared to phase 1 SAD trial. The decrease in exposure may contribute to the linearity of yimitasvir in phase 1b trial.
Food status was a significant covariate affecting the absorption rate (Ka) and bioavailability (F). In this population PK analysis, food was classified into three categories. Subjects who took the drug under fasted and fed (high-fat meal) condition were classified as food = 0 (as reference) and food = 2, respectively, while subjects in phase 1b trial who administered yimitasvir in the evening after dinner more than 4 h were classified as food = 1. Administration with a high-fat meal or in the evening after dinner more than 4 h resulted in a 28.9% and a 38.5% decrease in AUCss, a 10.0% and 3.52% decrease in Ctrough,ss, and a 46.1% and 58.9% decrease in Cmax,ss, respectively (Figure 4). The results from the population PK analysis were consistent with the results from previous studies. The decrease in steady state exposures might be due to the solubility of yimitasvir. Yimitasvir exhibited a pH-dependent solubility profile. In the fasted condition, yimitasvir solubility increased due to a low gastric pH in the stomach. However, a high-fat meal resulted in higher gastric pH for drug dissolution reduction [14]. Whether the decreased exposure after a high-fat meal would be clinically significant was not clear. It was recommended that yimitasvir was administered at least 2 h before or after a meal.
Gender was found to be a significant covariate for yimitasvir CL/F. Female subjects had lower apparent clearance than male subjects. The steady state exposures (AUCss, Ctrough,ss, Cmax,ss) in female subjects were 15.1-54.0% higher than male subjects. Baseline ALT was another significant covariate on Cl/F. The apparent clearance decreased with the increase of baseline ALT.
There was no difference in PK parameters between patients and healthy volunteers, except for parameter Td, which was a little longer in healthy volunteers than that in patients. The difference in Td between the two kinds of population did not result in exposure differences.
In phase 2 clinical trial, yimitasvir 100 or 200 mg was administered once daily for consecutive 12 weeks in combination with 400 mg sofosbuvir in HCV infection patients. The primary endpoint of 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. No dose-response relationship for efficacy and safety was identified in phase 2 clinical trial. Considering the high response rate and favorable safety profiles of yimitasvir in phase 2 clinical study, the significant covariates of gender and baseline ALT on clearance was not clinically relevant.
Except for gender, other baseline demographics such as age and BW had no effect on yimitasvir PK properties. It seems that there is no need to adjust dosage based on these factors. But due to the small sample size of phase 2 study, this conclusion should be further validated in a larger patient population.
This is the first time to establish a population PK model of a new HCV NS5A inhibitor, yimitasvir, in Chinese healthy volunteers and patients with chronic HCV genotype 1 Infection. It is very helpful for us to know statistically significant covariates affecting the pharmacokinetic property of yimitasvir. This work can be used as a basis for subsequent population PK model development including more patient data from phase 3 trial.
The population pharmacokinetic model was demonstrated to be appropriate and effective to describe the pharmacokinetics of yimitasvir in Chinese population. Food status, disease status (healthy volunteers vs patients), gender and baseline ALT were identified as statistically significant covariates to affect yimitasvir pharmacokinetics. High-fat meal decreased absorption rate and bioavailability, so it is recommended to take yimitasvir at least 2 h before or after a meal. Considering the favorable safety profile of yimitasvir and 100% SVR12 rate in phase 2 study, the impact of gender and ALT on yimitasvir exposure was not considered clinically relevant. This conclusion should be further validated in a larger patient population from phase 3 clinical trial.