A First-in-Human Trial of GLS4, a Novel Inhibitor of Hepatitis B Virus Capsid Assembly, following Single- and Multiple-Ascending-Oral-Dose Studies with or without Ritonavir in Healthy Adult Volunteers.

GLS4 is a novel inhibitor of the hepatitis B virus (HBV) capsid assembly with inhibitory activities against nucleot(s)ide-resistant HBV strains. This study investigated the pharmacokinetics, safety, and tolerability of GLS4 and the effects of food and ritonavir in healthy adults. GLS4 was administered in a single-ascending-dose study over 1 to 240 mg and multiple-ascending-dose study that ranged from 30 mg once daily to 180 mg three times daily. The drug interaction study included sequential design (day 1 for 120 mg GLS4 alone, day 5 for 100 mg ritonavir alone, followed by 9 days of both drugs) and a placebo control (9 days of both 240 mg GLS4 and 100 mg ritonavir). The results showed that the steady-state trough concentration of multiple dosing of GLS4 alone was significantly lower than the 90% effective concentration of 55.7 ng/ml, even with increasing dosing frequency and dosage. An initial dose of 100 mg ritonavir significantly boosted plasma concentration at 24 h of 120 mg GLS4 from 2.40 to 49.8 ng/ml (geometric mean ratio, 20.7; 90% confidence interval, 17.0 to 25.3), while a milder effect was observed on the area under the curve from 0 to 24 h, with a 7.42-fold increase, and on the maximum concentration, with a 4.82-fold increase. The pharmacokinetics change in GLS4 persisted after 9 days of chronic dosing, with a trough concentration of 182 ng/ml. Both single and multiple doses of GLS4 up to 240 mg with or without ritonavir were well tolerated. These results support the investigation of a novel HBV treatment regimen containing GLS4 with 100 mg ritonavir added solely to enhance GLS4 concentrations in plasma. (This study was registered at the China Platform for Registry and Publicity of Drug Clinical Trials [http://www.chinadrugtrials.org.cn] under numbers CTR20132137 and CTR20150230.).

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).