生理药代动力学模型在创新药物评价中应用及其若干问题的思考

生理药代动力学模型（PBPK）是建立在机体生理学、解剖学、药物代谢和药物转运特性及其药物理化性质和药物与机体相互作用等基础上的。PBPK可以定量预测血浆和组织中药物和代谢产物浓度；病理状态下药代动力学；研究特殊人群中药代动力学；基于动物数据预测人体药代动力学；基于体外代谢和转运参数预测在体药代动力学；指导药物制剂评价；基于体外药物转运、代谢和药效学/毒性数据和PBPK-PD预测在体药效和毒性；预测药物相互作用；评估代谢酶和转运体对药物处置贡献等。本文旨在结合案例评述PBPK在创新药物评价中的应用及值得注意的若干问题。

Application of physiologically based pharmacokinetic model in drug development and several questions being thought

Physiologically based pharmacokinetic (PBPK) model is based on physiology, anatomy, enzymes for drug metabolism, characteristic of drug transport, physicochemical property of drug and drug-body interaction. Thus, PBPK model may quantitatively predict: concentration-time profiles of drug and its metabolites in plasma and tissues; pharmacokinetics of drug under disease status; pharmacokinetics of drug in special population; pharmacokinetics of drugs in human derived from experimental animals; in vivo pharmacokinetics of drugs based on in vitro parameters for metabolism and transport; pharmacokinetics of drugs from different formations; pharmacodynamics or toxicity of drugs based on in vitro parameters for metabolism, transport, activity or toxicity of drug; drug-drug interaction; individual contributions of enzymes and transporters to in vivo drug disposition. Here, we would review applications of PBPK model in drug development and several questions which should be thought through a series of examples.