生理药代动力学模型在新药研发及监管领域的应用现状

Applications of physiologically based pharmacokinetic modeling and simulation in drug development and regulatory science

生理药代动力学(PBPK)模型通过整合药物本身理化特征、动物/人体的生理生化特点及药物处置等因素,来描述药物在体内真实存在的结构中的药代动力学-药效学(PK/PD)行为,结果可进行体内外、不同种属、不同情形(年龄/疾病/用药模式)下的外推。PBPK模型根据其复杂程度分为"bottom-up"及"top-down"两种系统,随着对模型系统理解的深入、体外-体内外推(IVIVE)系统及计算机技术的发展,PBPK模型的应用近年来已从学术界扩展到业界及监管部门,对监管决策的影响表现在不同新药研发阶段直至上市说明书中相关信息的出现。本文旨在介绍PBPK模型的原理及在新药研发中的应用,分析新药注册资料中PBPK模型应用的范围及监管机构(欧洲药品管理局及美国食品药品监督管理局)对模型预测应用的主要关注点。

Physiologicaily based pharmacokinetic （PBPK） model simu- lates the pharmacokinetics/pharmacodynamics （PK/PD） behavior by in- tegrating the properties of drug into the structure of animal/human body on the basis of interplay among critical physiological, physicochemical and biochemical determinants, the result can extrapolate from in vitro to in vivo, animal to human and among different scenarios （age/disease/ dosing regimen）. There were basically two kinds of PBPK models based on the extent of complexity, named ＂bottom - up＂ and ＂top - down＂ o The deeper insight of mechanism of the model ,development of in vitro to in vivo extrapolation （IVIVE） and computer techniques helped greatly the application of the PBPK modeling from the academic field to pharma- ceutical industries and the regulatory agencies, regulatory decisions have been impacted in different drug developmental stages until recently the simulation results appeared on the drug label. PBPK applications in the recent submissions to Food and Drug Administration （FDA） and Euro- pean Medicines Agency （EMA）and the main concerns from regulatory agencies were analyzed, some drugs were demonstrated for which the PBPK simulations appeared on their labels.