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.
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