Safety, Tolerability and Pharmacokinetics of Yimitasvir Phosphate Capsule, a Novel Oral Hepatitis C Virus NS5A Inhibitor, in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVES: Yimitasvir is a novel oral hepatitis C virus non-structural protein 5A (NS5A) inhibitor. The aims of this first-in-human study were to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of yimitasvir in healthy adult Chinese volunteers and to assess the effect of food on yimitasvir pharmacokinetics. METHODS: Randomized, double-blind, placebo-controlled, single-ascending-dose (30, 100, 200 and 400 mg) and multiple-ascending-dose (100 and 200 mg once daily for 7 days) studies were performed in 32 and 24 subjects, respectively, in male and female adults. Additionally, the effect of food on yimitasvir pharmacokinetics was assessed with a crossover study in 15 male subjects. RESULTS: Yimitasvir was absorbed slowly after oral administration with a median time to maximum plasma concentration (Tmax) of 3.5-4.0 h. Increases in the maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to the last measurable time point (AUC0-t) were proportional to the dose of yimitasvir over a dose range of 30-100 mg, while increases were less than dose proportional over a dose range of 200-400 mg in part 1, indicating that absorption at the 200-mg dose was nearly saturated. The geometric mean terminal half-life of yimitasvir was 13.4-19.7 h in each cohort, supporting once-daily dosing. Faecal excretion of parent yimitasvir was the major route of elimination. Steady state was achieved following 5 days of dosing with minimal accumulation. A standardized high-fat meal decreased the rate and extent of absorption. All doses of yimitasvir were well tolerated. CONCLUSIONS: Yimitasvir, at single doses of 30-400 mg and multiple doses of 100-200 mg for 7 days, was well tolerated in healthy Chinese subjects. The results of this study formed the basis for the dosing schemes evaluated in a phase Ib study and subsequent phase II and phase III clinical studies. CLINICAL TRIAL REGISTRATION: This study was registered at the China Food and Drug Administration (Registration numbers: 2014L02064 and 2014L02065) and at http://www.chictr.org.cn (Nos. CTR20140854, CTR20150048 and CTR20150123).