模型引导新药研发模式:原理与案例

Model⁃informed drug development:principles and cases

模型引导药物研发(MIDD)是新药研发模式的重大转变,重点是根据血药浓度(即暴露,PK)与疗效/安全性(即效应,PD)的对应数据建立PK⁃PD模型,再根据研究目的设置模拟条件,分析典型人群和亚组人群的暴露⁃效应关系,以替代难以获得的剂量⁃效应关系,从而建立药物有效性和安全性的证据链。PK⁃PD模型可以整合体内与体外、动物与人体、成人与儿童、文献与试验、原剂型与新剂型、国内与国外等来源数据,解决广泛的临床关键问题。特别重要的是将新药研发的探索模式转变为模型预测的验证模式。因此MIDD不仅事关技术手段的变化,还涉及多学科研究数据的整合,更是研发战略和科学监管方式的转变,极大地提高了新药研发效率和成功率。本文基于MIDD成功案例,简述其基本原理、概念与方法、实施路径,并以抗银屑病单抗药为例,呈现MIDD工作模式。

Model⁃informed drug development(MIDD)is a major shift of new mode of drug development based on the establishment of PK⁃PD model using blood concentration⁃(i.e.,exposure,PK)and efficacy/safety(i.e.,response,PD)⁃corresponding data,in order to analyze exposure⁃response relationship,replace dose⁃response relationship that is difficult to obtain,and establish the chain of evidence on drug safety and efficacy.The above model can integrate data from in vitro and in vivo,animals and human beings,adults and children,literature and trials,original and new dosage forms,domestic and foreign trials,and other sources to solve a wide range of key clinical problems.It is particularly important to transform the exploration paradigm of new drug development into a model verification mode.Therefore,MIDD is not only related to the change of technical means,but also the integration of multidisciplinary research,as well as a change of research and development strategy and scientific regulatory.It greatly improves the efficiency and success rate of new drug research and development.Based on the summary of MIDD success cases,this paper tries to clarify the basic principle,concept and method,implementation path,and takes anti⁃psoriasis monoantibody as an example to establish a complete MIDD working mode.