新药研发中的定量系统药理学(QSP)模型与虚拟临床试验:发展及前沿应用  

Advances and applications of quantitative systems pharmacology modeling and virtual clinical trials in modern drug development

作　　者：赵宸 李改玲 王亚宁 ZHAO Chen;LI Gai-ling;WANG Ya-ning(School of Pharmacy,Nanjing Medical University,Nanjing 210000,China;First Affiliated Hospital of Nanjing Medical University,Nanjing 210000,China;Certara Inc,Shanghai 200000,China;Createrna Science and Technology,Wuhan 430000,China)

机构地区：[1]南京医科大学药学院,江苏南京210000 [2]南京医科大学第一附属医院,江苏南京210000 [3]科盛达(上海)医药咨询有限公司,上海200000 [4]武汉朗来科技发展有限公司,湖北武汉430000

出　　处：《药学学报》2023年第11期3296-3310,共15页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金项目(82204545);工信部、药监总局揭榜挂帅项目(人工智能辅助诊疗器械临床试验平台);江苏特聘医学专家人才项目;中国科协青年人才托举工程项目(NO.YESS20210160);江苏省前沿引领技术基础研究重大项目(BK20222008);江苏省科技厅创新能力建设项目(BM2021004);南京市生命健康科技专项(20210010);南京医科大学高层次引进人才基金(NMUR20210006)。

摘　　要：基于定量系统药理学(quantitative systems pharmacology,QSP)模型的药物转化研究是国际上新兴的前沿药物研发范式。通过构建覆盖多个生理尺度中疾病关联机制及药物-靶点相互作用的数学模型,QSP可系统性整合多模态的临床前和临床层面数据,并从机制角度动态描述疾病发生发展过程及定量预测药物干预后产生的药效和不良反应。因此,QSP模型模拟和其衍生的虚拟临床试验分析已被用于指导新靶点和新治疗策略的发现与评估、临床试验方案设计、生物标志物筛选和个体化治疗等,其可在多个层面高效提升药物的临床转化成功率。QSP的理念在欧美发达国家的新药研发产业已经历十余年的发展和实际应用,并已逐渐成为现代模型引导药物研发模式中的重要部分,而其在国内仍处于起步初期。本文将全面介绍QSP这一前沿方向的内涵与进展及其在全球创新药研发中的实际应用案例,为推动我国QSP领域的发展以及原创新药的研发提供重要参考与指导。Quantitative systems pharmacology(QSP)modeling is an emerging computational medicine approach with growing applications and significance in modern drug development.QSP models are generally formulated based on multiscale disease mechanisms and drug-target interactions,which makes them capable of integrating multimodal data from the preclinical and clinical space.This also enables them to generate quantitative characterization of the dynamic disease progression as well as high-throughput predictions of drug-induced efficacy and toxicity signals.Therefore,QSP modeling and model-based virtual clinical trials have been widely implemented to guide drug development,in scenarios such as target identification and assessment,clinical trial design,evaluation of combination therapy and biomarkers,and personalized medicine.In US and Europe,QSP modeling has been developing rapidly in the past 10 years and is now an integral part of the model-informed drug development paradigm;however,in China it is still a nascent field.Here we will present a comprehensive review of the recent advancements of QSP and its impact in modern drug development through a number of case studies.This review will provide guidance for the future drug development efforts and the growth of QSP practice in China.

关 键 词：定量系统药理学 虚拟临床试验 机制建模与模拟 模型引导的药物研发 转化医学 

分 类 号：R96[医药卫生—药理学]