基于PBPK/PD/TD模型的阿法替尼治疗非小细胞肺癌的个体化用药研究

表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）阿法替尼是非小细胞肺癌的常用药物，但不良反应发生率高，临床常减量使用。如何在降低不良反应的同时保证其药效是临床合理用药亟需解决的关键问题。生理药动学（PBPK）模型可预测药物瘤内及正常组织浓度并可关联药效学（PD）和安全性（TD），是描述剂量-暴露-效应（D-E-R）关系的重要手段。国内外尚无能够预测人体EGFR-TKI瘤内浓度的PBPK模型研究，及相应的PBPK/PD/TD模型研究。本课题组以阿法替尼作为模型药物，应用PBPK模型成功模拟了药物在健康人和肺癌患者的血药浓度。下一步拟通过利用体外-体内相关性外推方法，结合肿瘤特征，构建能够预测药物瘤内及正常组织浓度的PBPK/PD/TD模型，定量预测既安全又有效的合理给药剂量范围，指导阿法替尼个体化用药方案的制定。本研究为小分子靶向药的临床个体化给药提供重要的方法学和治疗学参考。

Afatinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used in non-small-cell lung cancer (NSCLC) patients, but its high incidence of adverse drug reactions makes it often necessary to adjust the dose for the patients. Therefore, how to mitigate the adverse drug reactions while at the same time ensure its efficacy is a key problem that need to be solved in clinical rational drug use. Physiologically-based pharmacokinetic (PBPK) model can predict drug concentrations in the tumor cells and normal tissues so that it can be correlated to pharmacodynamic (PD) and toxicodynamic (TD) models, which is an important method to describe the relationship between dose - exposure - effect (D-E-R) relationships. Currently, there is no published study on PBPK model that can predict the intratumoral concentration of EGFR-TKIs in human, and therefore no related study on PBPK/PD/TD model of EGFR-TKI at home and abroad. Our research group choose afatinib as a model drug, we have used PBPK model to successfully predict the blood concentration of afatinib in healthy volunteers and cancer patients. Our research plan is to construct a PBPK/PD/TD model that can predict the concentration of drugs in tumor cells and normal tissues by using the in vitro and in vivo correlation extrapolation method, and by combining with tumor characteristics, to quantitatively predict the effective and safe dose range that is suitable for patients, and to guide the individualized therapy of afatinib in the clinical use. This study provides an important methodological and therapeutical reference for the individualized therapy of small molecule targeted drugs.