基于异植瘤小鼠的抗肿瘤药PK/PD模型:历史回顾、研究进展与应用实践  

Pharmacokinetic/pharmacodynamic models of anti-tumor agents in xenograft mice:historical review,recent advances,and application in drug development

作　　者：胡宽 花开 杨劲[1] HU Kuan;HUA Kai;YANG Jin(Center of Drug Metabolism and Pharmacokinetics,School of Pharmaceutical Sciences,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学药学院药物代谢研究中心,江苏南京210009

出　　处：《药学学报》2020年第11期2580-2594,共15页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金青年科学基金资助项目(81903702)。

摘　　要：异植瘤小鼠是广泛应用于抗肿瘤研究的临床前疾病动物模型。基于异植瘤小鼠的抗肿瘤药PK/PD建模是一种利用异植瘤小鼠实验数据与非线性混合效应模型法描述给药后"剂量-血药浓度-生物标志物水平-肿瘤体积"经时过程的方法。可基于模拟优化剂量与给药方案,评价抗肿瘤治疗联合用药方案协同效能,搜寻优效联用剂量组合,初步预测药物在人体的有效剂量与抗肿瘤效能,定量地阐释药物作用于靶点后生物标志物浓度变化所驱动的肿瘤增长抑制机制。本文系统地回顾了主流抗肿瘤药PK/PD模型的诞生背景、适用范围与应用局限,详细综述了创新抗肿瘤药PK/PD模型研究进展,并从作用机制探索、联合用药优化以及临床转化预测方面列举了PK/PD模型在抗肿瘤药物研究中的应用实践。Xenograft mice are preclinical animal models of tumors and are widely utilized in anti-tumor research.PK/PD modeling of anti-tumor agents is an approach that can capture the time profile of the"dose-plasma concentration-biomarker level-tumor volume"process based on experimental data from xenograft mice using a non-linear mixed-effect model.PK/PD modeling can help optimize the dosing regimen for anti-tumor therapy,evaluate any synergistic effect and help identify an optimal schedule for combination therapy,as well as providing a preliminary estimate of a drug’s efficacy and anti-tumor potency in the human body.PK/PD modeling can also help by quantitatively explaining the mechanism of the tumor-inhibitory effect as indicated by changes in biomarker levels after a drug acts on its target.This article provides a systematic summary of the background,application range,and limitations of the mainstream anti-tumor agent PK/PD models.Recent advances in model structure development are reviewed in detail.Finally,we discuss promising applications of PK/PD models in anti-tumor medicine development from the perspective of a drug’s mechanism of action,optimization of combination therapy schedules,and their clinical translation.

关 键 词：抗肿瘤治疗 药动学/药效学模型 联合治疗 异种移植小鼠 定量药理学 

分 类 号：R917[医药卫生—药物分析学]