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

doi:10.5246/jcps.2015.12.099

中国药学(英文版) ›› 2015, Vol. 24 ›› Issue (12): 773-779.DOI: 10.5246/jcps.2015.12.099

• 【研究论文】 • 下一篇

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

王鹤川², 李良², 任宇鹏², 周田彦¹, 卢炜^1*

1. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学医学部药学院药剂学系, 北京 100191

收稿日期:2015-06-28 修回日期:2015-08-30 出版日期:2015-12-22 发布日期:2015-09-15
通讯作者: Tel.: 86-10-82801717, E-mail: luwei_pk@bjmu.edu.cn

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

Hechuan Wang², Liang Li², Yupeng Ren², Tianyan Zhou¹, Wei Lu^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2015-06-28 Revised:2015-08-30 Online:2015-12-22 Published:2015-09-15
Contact: Tel.: 86-10-82801717, E-mail: luwei_pk@bjmu.edu.cn

摘要/Abstract

摘要：

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。

关键词: 索他洛尔, 来地帕韦, GS331007, 群体药物动力学模型, 丙型肝炎, 基于模型的荟萃分析

Abstract:

A tablet consisting of direct-acting antiviral agents, ledipasvir (a NS5A protein inhibitor) and sofosbuvir (a NS5B 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 systematicpublication 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-orderabsorption was used for the modeling of GS331007. Absorption lag was observed in concentration-time profiles of both ledipasvirand 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.

Key words: Ledipasvir, Sofosbuvir, GS331007, Population pharmacokinetic modeling, Hepatitis C, Model-based meta-analysis

中图分类号:

R944.9

Supporting: Janssen Research & Development, China; Pfizer Scholarship for Pharmacometrics during this project.

王鹤川, 李良, 任宇鹏, 周田彦, 卢炜. 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[J]. 中国药学(英文版), 2015, 24(12): 773-779.

Hechuan Wang, Liang Li, Yupeng Ren, Tianyan Zhou, Wei Lu. Model-based meta-analysis of pharmacokinetics of direct-acting antiviral agents, ledipasvir and sofosbuvir, in healthy subjects and chronic HCV patients[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(12): 773-779.

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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

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

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