Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype Ⅰ chronic hepatitis C  

作　　者：He-chuan WANG Yu-peng REN Yue QIU Jenny ZHENG Gai-ling LI Chuan-pu HU Tian-yan ZHOU Wei LU Liang LI 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China [2]Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [3]Clinical Pharmacology, Janssen (China) Research & Development Center, Beijing 100025, China [4]Model Based Drug Development, Janssen Research and Development, LLC, Spring House, PA 19477, USA

出　　处：《Acta Pharmacologica Sinica》2018年第1期140-153,共14页中国药理学报（英文版）

摘　　要：In order to develop an integrated pharmacokinetic/viral dynamic （PK/VD） model to predict long-term virological response rates to daclatasvir （DCV） and asunaprevir （ASV） combination therapy in patients infected with genotype 1 （GT1） chronic hepatitis C virus （HCV）, a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The ICso values of DCV and ASV were estimated to be 0.041 and 2.45 pg/L, respectively, in GTIA patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GTIA patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GTIB patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.In order to develop an integrated pharmacokinetic/viral dynamic （PK/VD） model to predict long-term virological response rates to daclatasvir （DCV） and asunaprevir （ASV） combination therapy in patients infected with genotype 1 （GT1） chronic hepatitis C virus （HCV）, a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The ICso values of DCV and ASV were estimated to be 0.041 and 2.45 pg/L, respectively, in GTIA patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GTIA patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GTIB patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.

关 键 词：chronic hepatitis C daclatasvir asunaprevir PHARMACOKINETICS viral dynamics modeling and simulation NONMEM 

分 类 号：R0[医药卫生]