Nan Zhao1, Ran Xie1, Xia Zhao1, Hong Zhao2, Bo Jia1, Yingjun Zhang3, Lin Luo3, Zhangma Huang3, Jing Li3, Xingan Wang3, Huan Yan3, Bixia He3, Hongming Xie3, Qingyun Ren3, Yimin Cui4. 1. Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China. 2. Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing, 100034, China. 3. Sunshine Lake Pharma Co., Ltd., Dongguan, 523871, China. 4. Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China. cui.pharm@pkufh.com.
Abstract
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).
RCT Entities:
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).
Authors: Chih-Wei Lin; Sandeep Dutta; Armen Asatryan; Haoyu Wang; Jack Clifton; Andrew Campbell; Wei Liu Journal: Clin Pharmacol Drug Dev Date: 2017-05-02
Authors: D A Wilfret; J Walker; K K Adkison; L A Jones; Y Lou; J Gan; S Castellino; C L Moseley; J Horton; M de Serres; A Culp; I Goljer; W Spreen Journal: Antimicrob Agents Chemother Date: 2013-07-29 Impact factor: 5.191
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