A physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic profiles of ZSP1601, a novel pan-phosphodiesterase inhibitor
10.16438/j.0513-4870.2021-1024
- VernacularTitle:采用生理药动学模型预测新型泛磷酸二酯酶抑制剂ZSP1601在人体中的药动学
- Author:
Yi-fan ZHANG
1
;
Ye XU
1
;
Hai-jun LI
2
;
Xiao-xin CHEN
2
;
Song-bo XU
2
;
Jia LIU
1
;
Zhi-jie WANG
1
;
Da-fang ZHONG
1
Author Information
1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2. Guangdong Raynovent Biotech Co., Ltd., Guangzhou 510663, China
- Publication Type:Research Article
- Keywords:
physiologically-based pharmacokinetic model;
pan-phosphodiesterase inhibitor;
nonalcoholic steatohepatitis;
clinical pharmacokinetics
- From:
Acta Pharmaceutica Sinica
2021;56(12):3540-3546
- CountryChina
- Language:Chinese
-
Abstract:
ZSP1601, a novel pan-phosphodiesterase inhibitor is in development for the treatment of nonalcoholic steatohepatitis. A physiologically-based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of ZSP1601 in human. The PBPK model following intravenous and oral dose of ZSP1601 in rats and dogs was firstly built using preclinical in vitro and in vivo data. The PBPK model in human was then built based on models in animal. The in vitro-in vivo extrapolation (IVIVE) method and some allometric scaling methods were used to predict the clearance in human, respectively. The PBPK models using IVIVE and allometry of unbound CL plus the rule of exponents methods predicted the pharmacokinetics of ZSP1601 in healthy Chinese subjects successfully. The predicted parameters Cmax and AUC following single oral dose administration were within 0.5-2 folds of the observed data. The model was optimized and the final model was used to predict the pharmacokinetics of ZSP1601 in North European Caucasian, Geriatrics, Obese and Morbidly Obese, respectively. Animal studies were approved by the Animal Management and Use Committee of Suzhou AppTec Inc., and the approved No. is SZ20140916.
