药物相互作用临床研究策略及基于生理的药动学模型应用进展

doi:10.12092/j.issn.1009-2501.2019.10.002

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (10): 1085-1091.doi: 10.12092/j.issn.1009-2501.2019.10.002

药物相互作用临床研究策略及基于生理的药动学模型应用进展

李丽，杨进波

国家药品监督管理局药品审评中心，北京 100038

收稿日期:2019-09-03 修回日期:2019-10-12 出版日期:2019-10-26 发布日期:2019-10-28
通讯作者: 杨进波，男，博士，主任药师，主要从事临床和药理学相关审评工作。 Tel：010-85243210 E-mail：yangjb@cde.org.cn
作者简介:李丽，女，硕士，主管药师，主要从事临床药理学相关审评工作。 Tel：010-85243178 E-mail：lil@cde.org.cn
基金资助:
重大新药创制《药物一致性评价关键技术与标准研究》（2017zx09101001）

Strategies of clinical drug-drug interaction studies and application progress of physiologically-based pharmacokinetic model

LI Li, YANG Jinbo

Center for Drug Evaluation, National Medical Products Administration，Beijing 100038, China

Received:2019-09-03 Revised:2019-10-12 Online:2019-10-26 Published:2019-10-28

摘要/Abstract

摘要：

药物-药物相互作用（DDI）会引起不良事件或导致疗效降低，是药物治疗常见的问题之一，因此创新药需对DDI进行研究。本文将对临床DDI研究的总体思路和研究类型进行综述性介绍。数学模型，尤其是基于生理的药动学模型（PBPK）在DDI研究中的作用日益广泛，其可以整合人体生理系统参数、药物理化性质和机理性药动学数据以提早预测人体内的药物药动学特征，PBPK模型逐渐成为辅助甚至替代部分DDI研究的重要研究方法。目前，PBPK已经在美国、欧盟的临床DDI研究中得到广泛应用，并有相关指南出台指导应用，但我国相关指南尚未颁布。因此，从药物研发的实效性考虑，本文也将综述PBPK在临床DDI研究的策略选择、试验设计、试验豁免及临床用药方面的应用进展，并简要介绍其预测力评价标准以及研究报告内容，以期为PBPK在我国创新药DDI临床开发的科学应用提供支持。

关键词: 药物-药物相互作用, 基于生理的药动学模型, 临床研发

Abstract:

Drug-drug interaction (DDI) might cause reduced efficacy, even induce severe safety issues of drugs, which might be one of the most common concerns in clinical therapy. Therefore, clinical DDI should be investigated during new drug development before marketing. This paper reviewed the overall research strategy and types of DDI studies. Regarding various mathematical models, physiologically-based pharmacokinetics model (PBPK) had become an important tool to assist or even partially replace DDI studies by integrating human physiological parameters, drug chemical/physical data, and drug mechanistic pharmacokinetic data to predict pharmacokinetic characteristics. Recently, PBPK analyses had been extensively applied in DDI studies in America and Europe, where relevant guidance documents had been released to direct such studies，whereas Chinese guidance on PBPK was absent. By seeing the power of model informed drug development to improve new drug research efficiency, in this review, we introduced the application of PBPK model in study design, waiver of DDI studies, and so on. How to evaluate the prediction accuracy and report PBPK study results was briefly summarized as well. Hopefully this paper could update knowledge and support new drug development in China.

Key words: drug-drug interaction, physiologically-based pharmacokinetic model, clinical developme

中图分类号:

R969.1

李丽，杨进波. 药物相互作用临床研究策略及基于生理的药动学模型应用进展[J]. 中国临床药理学与治疗学, 2019, 24(10): 1085-1091.

LI Li, YANG Jinbo. Strategies of clinical drug-drug interaction studies and application progress of physiologically-based pharmacokinetic model[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(10): 1085-1091.

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药物相互作用临床研究策略及基于生理的药动学模型应用进展

Strategies of clinical drug-drug interaction studies and application progress of physiologically-based pharmacokinetic model

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