Interactions Between Cytotoxic and Antiangiogenic Drugs

描述(申请人提供)：该项目旨在研究血管生成抑制剂[AIS]和细胞毒性药物(一种治疗实体肿瘤的新兴化疗策略)组合的药代动力学[PK]和药效学[PD]基础。有两种类型的人工智能：一种是标准的人工智能，通常针对的是生长因子受体，另一种是节律剂量的细胞毒药物[MDCDs]，即以长时间低剂量计划给药的传统细胞毒药物。成功的抗血管生成治疗可能会改变一些生理变量，如血流、间质液体压力和血管通透性，这些变量可以介导联合应用细胞毒药物的肿瘤浓度的药效学[PD]变化。我们在过去的资助周期中已经证明，这种AI：细胞毒药物的相互作用可以导致细胞毒药物在肿瘤中的浓度降低和增加。本申请中提出的研究将表征人工智能的PK/PD，无论是标准的ALS还是MDCDs，单独以及与常规剂量的细胞毒药物联合使用。该项目将使用异种移植的大鼠胶质瘤模型，在皮下和脑内模型位置，改造成过表达血管内皮生长因子[VEGF]，这是肿瘤血管生成的关键细胞因子。将获得一系列广泛的PK测量，包括基于肿瘤微透析的测量，以及包括通过动态增强MRI测量血管渗透性的PD测量。合并的PK/PD数据将被转换为基于生理学的混合PK/PD模型，该模型将提供一个机制框架来表征药物传输相互作用，并作为放大模型以预测人类肿瘤药物浓度的基础。该项目的最终目标是清楚地了解影响药物处置的变量，并推导出可用于设计ALS和细胞毒药物组合的最佳剂量方案的量化工具。

DESCRIPTION (provided by applicant): This project seeks to investigate the pharmacokokinetic [PK] and pharmacodynamic [PD] basis of combinations of angiogenesis inhibitors [AIs] and cytotoxic drugs, an emerging chemotherapeutic strategy for the treatment of solid tumors. Two types of AIs are available; either standard AIs, often targeted to growth factor receptors, or metronomic-dosed cytotoxic drugs [MDCDs], conventional cytotoxic agents administered in protracted low-dose schedules. Successful antiangiogenic therapy may alter a number of physiological variables, such as blood flow, interstitial fluid pressure, and vascular permeability, which can mediate pharmacodynamic [PD] changes in tumor concentrations of co-administered cytotoxic drugs. We have demonstrated in the past funding cycle that such AI: cytotoxic drug interactions can result in both decreased and increased tumor concentrations of the cytotoxic drugs. Studies proposed in this application will characterize the PK/PD of the AIs, either standard Als or MDCDs, alone and in combination with regular-dosed cytotoxic drugs. The project will use a rat xenograft glioma model, both at subcutaneous and intracerebral model locations, engineered to over express vascular endothelial growth factor [VEGF], a key cytokine in tumor angiogenesis. An extensive series of PK measurements, including those based on tumor microdialysis, and PD measurements including the measurement of vascular permeability by dynamic-contrast enhanced MRI will be obtained. The combined PK/PD data will be cast into hybrid physiologically based PK/PD models that will provide a mechanistic framework to characterize drug transport interactions, and also serve as a basis to scale-up the models to predict human tumor drug concentrations. The ultimate goals of the project are to provide a clear understanding of the variables that impact on drug disposition, and to derive quantitative tools that can be used to design optimal dosing regimens for combinations of Als and cytotoxic drugs.