A Physiologically Based Pharmacokinetic Model of HSK3486 and Extrapolation to Special Populations and Drug-Drug Interactions
作者单位：Phase I UnitClinical Pharmacology Research CenterPeking Union Medical College Hospital and Chinese Academy of Medical Sciences
会议名称：《2018年中国药理学会定量药理学专业委员会学术年会》
会议日期：2018年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
关 键 词：PBPK Drug-drug interaction HSK3486 Pharmacokinetics
摘 要：Objectives:HSK3486 is a novel optically 2,6-disubstituted alkylphenol as general anesthetics,it is widely metabolized by CYP450 enzymes in human *** purpose of this study is to develop a physiologically based pharmacokinetic(PBPK) model for HSK3486 to provide insights into its pharmacokinetic properties in special population(liver cirrhosis,renal failure patient and geriatric),and to explore the potential risks of drug-drug interaction(DDI).Methods:Based on the platform of Simcyp population-based simulator(versin 16 and 17,Sheffield,UK),drug physicochemical properties such as molecular weight(M.W),oil-water partition coefficients(log P),free fraction in human plasma(f),and drug elimination data like in vitro intrinsic clearance(CL) by recombinant CYP1 A2,CYP2 A6,CYP2 B6,CYP2 C8,CYP2 C9,CYP2 C19,CYP2 D6,CYP2 E1,CYP3 A4,CYP3 A5 enzymes,as well as drug distribution data were integrated to develop a PBPK *** initial model was validated using observed pharmacokinetic data in Chinese healthy ***,the validated model was used to extrapolate the pharmacokinetic profiles in special population by replacing population module in Simcyp ***,inhibitors or inducers for the key metabolic enzymes of HSK3486 were selected and integrated into PBPK *** pharmacokinetic profiles were separately simulated for a single dose of HSK3486 alone and combination after 7 days successive administration of *** area under the curve(AUC) ratio with or without inhibitor was calculated for evaluate the DDI ***:The validation results demonstrated that the PBPK model could accurately predict the pharmacokinetic characteristics of HSK3486 in Chinese *** simulated pharmacokinetic parameters such as maximum concentration(C) and AUC of HSK3486 were within 1.5-fold of that *** AUC ratio of HSK3486 at presence and absence inhibitors or inducers were ranged from 0.94 to ***:A PBPK model was successfully developed to