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  

A physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic profiles of ZSP1601,a novel pan-phosphodiesterase inhibitor

作　　者：张逸凡 徐叶 李海军 陈小新 徐松波 刘佳 王志杰 钟大放 ZHANG Yi-fan;XU Ye;LI Hai-jun;CHEN Xiao-xin;XU Song-bo;LIU Jia;WANG Zhi-jie;ZHONG Da-fang(Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Guangdong Raynovent Biotech Co.,Ltd.,Guangzhou 510663,China)

机构地区：[1]中国科学院上海药物研究所,上海201203 [2]广东众生睿创生物科技有限公司,广东广州510663

出　　处：《药学学报》2021年第12期3540-3546,共7页Acta Pharmaceutica Sinica

基　　金：国家十三五“重大新药创制”专项(2018ZX09201002-002-001)。

摘　　要：ZSP1601是一种新的泛磷酸二酯酶抑制剂,临床拟用于非酒精性脂肪肝炎的治疗,目前处于早期临床研究阶段。本文拟建立ZSP1601的人体生理药动学(PBPK)模型,用于预测药物在人体的药动学行为。首先根据非临床体外和体内实验结果建立大鼠和犬静脉及口服给药的PBPK模型。在此基础上构建人体PBPK模型,分别比较了体外体内外推法(IVIVE)和几种异速放大方法的预测结果。采用IVIVE和游离分数校正的幂指数法建立的模型模拟ZSP1601单次给药的C_(max)和AUC均在实测值的0.5~2倍之内。利用优化并验证的PBPK模型模拟了ZSP1601在北欧高加索人群、老年人、肥胖及病理性肥胖人群的药动学。动物实验经苏州药明康德新药开发有限公司动物管理及使用委员会批准(批件号为SZ20140916)。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 C_(max)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.

关 键 词：生理药动学模型 泛磷酸二酯酶抑制剂 非酒精性脂肪肝炎 临床药动学 

分 类 号：R969[医药卫生—药理学]