Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China.
Department of Infectious Diseases, Center for Liver Disease, Peking University First Hospital, Beijing, 100034, China.
Clin Drug Investig. 2019 Jul;39(7):671-681. doi: 10.1007/s40261-019-00791-8.
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.
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.
Yimitasvir was absorbed slowly after oral administration with a median time to maximum plasma concentration (T) of 3.5-4.0 h. Increases in the maximum plasma concentration (C) and area under the concentration-time curve from 0 to the last measurable time point (AUC) 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.
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.
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).
依米他韦是一种新型的口服丙型肝炎病毒非结构蛋白 5A（NS5A）抑制剂。本首次人体研究的目的是评估健康成年中国志愿者单剂量和多剂量依米他韦的安全性、耐受性和药代动力学，并评估食物对依米他韦药代动力学的影响。
在男性和女性成年人中，分别进行了随机、双盲、安慰剂对照、单剂量递增（30、100、200 和 400mg）和多剂量递增（100 和 200mg 每日一次，共 7 天）研究，共有 32 和 24 名受试者参加。此外，还在 15 名男性受试者中进行了交叉研究，以评估食物对依米他韦药代动力学的影响。
依米他韦口服后吸收缓慢，中位达峰时间（T）为 3.5-4.0h。依米他韦的最大血浆浓度（C）和从 0 到最后可测量时间点的浓度-时间曲线下面积（AUC）随剂量增加呈比例增加，在 30-100mg 剂量范围内，剂量范围为 200-400mg 时，增加量小于剂量比例，表明 200mg 剂量时吸收接近饱和。依米他韦的几何平均终末半衰期在每个队列中为 13.4-19.7h，支持每日一次给药。粪便中母药依米他韦的排泄是主要的消除途径。给药 5 天后达到稳态，蓄积最小。标准化高脂肪餐可降低吸收速度和程度。所有剂量的依米他韦均耐受良好。
依米他韦单剂量 30-400mg 和多剂量 100-200mg 连续 7 天给药，在健康中国受试者中耐受良好。本研究结果为后续 Ib 期研究以及随后的 II 期和 III 期临床研究中评估的给药方案提供了依据。
该研究在中国食品药品监督管理局（注册号：2014L02064 和 2014L02065）和 http://www.chictr.org.cn（注册号：CTR20140854、CTR20150048 和 CTR20150123）进行了注册。
