Model-based meta-analysis of pharmacokinetics of direct-acting antiviral agents,ledipasvir and sofosbuvir,in healthy subjects and chronic HCV patients

直接作用抗病毒药物索他洛尔和来地帕韦在健康人群和慢性丙肝病人中基于模型的群体药物动力学荟萃分析（英文）

A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and GS331007.Zero-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of GS331007.Absorption lag was observed in concentration-time profiles of both ledipasvir and GS331007.To aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.

由直接作用抗病毒药物来地帕韦(NS5A蛋白抑制剂)和索他洛尔(NS5B聚合酶抑制剂)组成的复方片剂是第一个被批准用于临床的丙肝抗病毒治疗复方制剂。来地帕韦和索他洛尔的主要代谢物GS331007的基于模型的群体药物动力学荟萃分析定量描述了这两种药物的群体药物动力学特征。通过系统的文献检索收集来地帕韦和索他洛尔的药物动力学临床研究信息。401个GS331007群体水平数据点和188个来地帕韦群体水平数据点用于群体药物动力学模型化建设。两种药物均采用二室处置模型,采用零级吸收描述来地帕韦的吸收过程,混合的零级和一级吸收过程用于拟合GS331007药时曲线吸收相,在两种药物的药时曲线中均观察到了吸收滞后现象。本研究建立的群体药物动力学模型为今后来地帕韦和索他洛尔的群体药物动力学-病毒动力学联合模型研究奠定了基础,同时为未来的直接作用抗病毒药物的开发提供了一些指导和帮助。