模型引导的药物开发在抗体偶联药物领域的应用  

Application of model informed drug development in the field of antibody drug conjugates

作　　者：吴白杨 王凌 姜静[1,2] WU Bai-yang;WANG Ling;JIANG Jing(School of Pharmacy,Binzhou Medical University,Yantai 264003,China;RemeGen Co.,Ltd.,Yantai 264006,China)

机构地区：[1]滨州医学院药学院,山东烟台264003 [2]荣昌生物制药(烟台)股份有限公司,山东烟台264006

出　　处：《药学学报》2025年第2期288-299,共12页Acta Pharmaceutica Sinica

基　　金：山东省自然基金项目(R2021MH220);山东省泰山产业领军人才项目。

摘　　要：抗体偶联药物(antibody drug conjugates, ADC)作为抗肿瘤治疗的前沿技术,近年来取得了显著进展。ADC通过连接子将高活性小分子毒素与高特异性抗体进行偶联,不仅能够实现对肿瘤细胞的精准打击,同时降低了药物的全身毒性,进而扩大了治疗的有效性和安全性窗口。然而,由于ADC分子设计的复杂性,其疗效和安全性受多种因素影响。模型引导的药物开发(model informed drug development, MIDD)是一种通过数学和统计模型进行建模和模拟,对药物研发进行定量分析和决策指导的方法。这种方法为新药研发提供强大的工具支持。通过MIDD整合ADC相关的多方面数据和信息,有助于理解ADC的复杂机制、药代动力学和药效学等作用特征,为优化ADC研发流程和临床转化决策提供独特见解。本文将介绍MIDD和ADC的基本概念,并浅析MIDD在ADC研发不同阶段的应用案例,旨在为ADC的发展提供有益参考。Antibody drug conjugates(ADC)have emerged as a cutting-edge technology in anti-tumor treatment,making significant strides in recent years.ADC couple a highly active small molecule toxin payload to highly specific antibodies through a linker,enabling precise targeting of tumor cells while reducing systemic toxicity,thereby expanding the therapeutic window.However,due to the complexity of ADC molecule design,its efficacy and safety are influenced by various factors.Model-informed drug development(MIDD)is a powerful tool that utilizes various mathematical models for modeling and simulation to conduct quantitative analysis,guiding drug development and decision-making.By integrating multi-faceted data and information using mathematical models,it is possible to gain insights into the complex mechanisms,pharmacokinetics,and pharmacodynamics of ADC,providing unique perspectives for optimizing ADC development processes and clinical translation decisions.This review will introduce the basic concepts of MIDD and ADC and discuss application cases of MIDD in different stages of ADC development,aiming to provide beneficial references for the advancement of ADC.

关 键 词：模型引导的药物开发 抗体偶联药物 建模与模拟 药代动力学/药效动力学 定量系统药理学 生理药代动力学 群体药代动力学 

分 类 号：R914[医药卫生—药物化学]