抗VEGF类药物肿瘤组织生理-药代-药效（PB-PK-PD）模型在肿瘤个体化化疗中的应用研究

Pharmacokinetic and pharmacodynamic (PK-PD) model is the most important method to develop individual therapy in chemotherapy. Our former researches had shown that plasma PK-PD model of anti-VEGF (vascular endothelial growth factor) agents could not be better to reflect the relationship between therapeutic efficiency and dosage. In order to address this problem, we setup a new model and use it in individual chemotherapy: At first we setup a model-based physiological (PB) to describe the relationship of tumor VEGF level with tumor microenvironment such as the rate of VEGF secretion, VEGF receptors numbers and the tumor blood flow. This PB model will predict process how the free VEGF secrets and disappears in the tumor. Then hybrid physiologically based PK model (PB-PK) will be developed, in which describes the effects of the dosage and dosing interval, the pharmacokinetics parameters of VEGF and PB in the tumor. Finally we select tumor blood flow inhibition and tumor size as PD end point, fit into PB- PK-PD model, and then use it in individual chemotherapy. The development of tumor PB-PK-PD model for anti-VEGF agents is useful to select dosing regiments including dosage and dosing interval to achieve desired PD profiles. Our model provides a new method to develop individual chemotherapy for anti-VEGF agents.

基于药代动力学-药效学模型（PK-PD模型）选择最佳剂量是抗癌药物个体化给药发展的方向。本课题组前期研究显示抗血管生长因子（VEGF）类药物的血浆PK-PD模型并不能很好的反映其药物剂量与疗效的关系，为了解决这一问题，本课题首先研究肿瘤组织VEGF生成和消除特征，建立其与细胞分泌VEGF速率、表达VEGF受体以及肿瘤血液流速的生理模型（PB），并以此拟合肿瘤组织内抗VEGF类药物浓度与给药剂量、给药间隔及药代参数的PB-PK模型；最终建立以肿瘤血流抑制和肿瘤缩小为药效指标的肿瘤组织PB-PK-PD模型并进行肿瘤个体化给药的初步研究。本课题的实施将建立抗VEGF类药物肿瘤组织PB-PK-PD模型，该模型可用于肿瘤患者临床给药剂量和给药频率的调整，从而达到抗-VEGF类药物的个体化给药目的。

缺乏有效的疗效替代指标和合适的给药剂量确定方式一直是阻碍抗-血管生长因子（VEGF）类药物临床应用的主要原因。本课题组关于抗-VEGF类药物的临床试验显示此类药物能有效清除血浆VEGF和抑制肿瘤血液的灌注，但这两个指标与剂量和疗效不存在相关性，不能架接剂量和疗效的关系。为了解决这一问题，本课题首先检测Kras转基因工程小鼠给药前、后肿瘤组织VEGF微环境、生理性能（细胞骨架、侵袭、转移基因）、血管状态（CD144、Tie-1）的改变，从而筛选出潜在的疗效替代指标。以替代指标为药效指标，肿瘤组织内抗-VEGF类药物浓度为PK指标，构建肿瘤组织内PB-PK-PD模型。本课题的实施将有助于确定抗-VEGF类药物有效人群及潜在的联合用药靶点，并可实施临床个体化给药，大大的降低用药盲目性和费用。