联合应用PBPK模型和PopPK模型助力儿科用药研发中的剂量选择:以利伐沙班为例  

The combined application of PBPK model and PopPK model in the dose selection of pediatric drug development:an example of rivaroxaban

作　　者：简伟哲 陈镕[1] 周田彦[1] JIAN Wei-zhe;CHEN Rong;ZHOU Tian-yan(Department of Pharmaceutics,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China)

机构地区：[1]北京大学药学院药剂系,北京100191

出　　处：《药学学报》2022年第10期3157-3162,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82073919)。

摘　　要：在儿科用药研发面临巨大挑战的背景下,模型引导的药物研发(model-informed drug development,MIDD)在儿科新药研发中日益受到重视。在指导剂量选择时,MIDD的核心内容包括基于生理的药物动力学(physiologically based pharmacokinetic,PBPK)模型和群体药物动力学(population pharmacokinetic,PopPK)模型的建立和仿真预测。PBPK模型用于开展临床试验前对儿科剂量进行预测,具有从成人PK外推至儿科PK的能力;PopPK模型用于从儿科临床数据中分析得到药物的PK特征,分析影响药物PK行为的关键协变量,指导个体化儿科用药。这两种模型各有优势与不足,需要在儿科新药研发各个阶段进行联合运用,互相补充,共同为儿童各年龄阶段的剂量选择发挥作用。本文以利伐沙班儿科用药研发为例,介绍PBPK模型和PopPK模型在儿科Ⅰ、Ⅱ、Ⅲ期临床试验中设计和验证给药方案的联合应用,为其他儿科用药研发中MIDD的应用提供参考。Model-informed drug development(MIDD)in the development of pediatric drugs is drawing more and more attention due to the insufficiency of subjects,lack of research on ontogeny,and the limitation of ethic.The core of MIDD used for dose selection includes the population pharmacokinetic(PopPK)model and physiologically based pharmacokinetic(PBPK)model,as well as model-based simulation and prediction.PBPK model has the advantage of predicting the optimal pediatric dose before the clinical trials and has the ability of extrapolation from adult model to pediatric model.PopPK model characterizes the pediatric PK feature based on the analysis of clinical data and can be used to explore the significant covariates,which is a power tool for individualized medicine in children.With their own advantages and disadvantages,PBPK and PopPK model should be jointly used in the pediatric drug development to refine the dose regimen for children at different ages.In this study,the pediatric drug development of rivaroxaban was taken as an example to introduce the combined application of PBPK model and PopPK model in the design and validation of pediatric dose regimen in PhaseⅠ,Ⅱ and Ⅲ trials,which may provide reference to MIDD in other pediatric drug development.

关 键 词：模型引导的药物研发 儿科药物 群体药物动力学模型 基于生理的药物动力学模型 利伐沙班 

分 类 号：R969[医药卫生—药理学]