摘要
小干扰RNA(small interfering RNA,siRNA)是以RNA干扰(RNAi)为基础的一类具有独特药代动力学特性和作用机制的药物,目前已有5种基于两种递送系统的siRNA药物上市获批,并且有越来越多的siRNA药物进入临床研究阶段。生理药代动力学(PBPK)建模是一种辅助药物开发和决策的可靠的工具,并且越来越被监管机构接受,PBPK模型在小分子和大分子领域广泛应用的背景下,在指导siRNA类药物开发方面仍然处于起步阶段。本文结合siRNA类药物的药代动力学特征,概述了siRNA类药物PBPK模型开发的现状及模型构建中所需的关键参数,以期为今后PBPK模型在siRNA类药物研发中的应用,及优化设计临床前试验获得关键数据提供一定的借鉴。
Small interfering RNAs(siRNAs)are an emerging class of RNA interference(RNAi)therapeutics with unique pharmacokinetic properties.Five siRNA drugs based on two delivery systems have been approved,and an increasing number of siRNA drugs have already moved to the clinical study phase.Physiologically-based pharmacokinetic(PBPK)modeling is a useful tool and has been demonstrated to have wide ranging utility in drug development and regulatory review.However,PBPK modeling is still in its infancy in guiding the development of siRNA-based drugs in the context of its widespread use in small and large molecule areas.This article reviews the pharmacokinetic profiles of siRNA drugs,outlines the current state of PBPK model building in siRNA drug development,and describes the key parameters required for model building.This article provides insights into the future applications of PBPK models and for optimizing the key parameters when building the model for siRNA drug development.
作者
李倩
陈锐
胡蓓
LI Qian;CHEN Rui;HU Pei(Clinical Pharmacology Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100730,China)
出处
《药学学报》
CAS
CSCD
北大核心
2022年第10期3146-3156,共11页
Acta Pharmaceutica Sinica
基金
中央高水平医院临床科研专项(2022-PUMCH-A-060)
北京市金桥工程种子基金(ZZ20047)。
关键词
RNA干扰
小干扰RNA
药代动力学
生理药代动力学
模型
关键参数
RNA interference
small interfering RNA
pharmacokinetics
physiological pharmacokinetics
modeling
key parameter
