) Chemotherapy of women with advanced-stage ovarian cancer achieves good initial results with only a limited impact on long-term disease outcomes, as over 80 percent of these patients eventually develop recurrent disease accompanied by a progressive increase in drug resistant tumors. Long-term outcomes might be improved through the development of new chemotherapy regimens, especially through incorporation of agents that exhibit pharmacological synergy. Toxicity of these new regimens has been substantial, and management of hematologic toxicity has thus assumed the dominant role in clinical trial design, without direct or indirect evidence that the desired biologic targets are actually being modulated within the tumor. The number of potential combinations and sequences in daunting, and many promises regimens will be overlooked using a conventional empiric approach to clinical trial design. The overall goals of this application will be to apply and integrate pharmacokinetic (PK) and pharmacodynamic (PD) principles in both preclinical models and clinical trials to select and optimize combination chemotherapy in ovarian cancer patients. We propose to utilize a syngeneic rat model of advanced epithelial ovarian cancer as a translational tool to address biologic questions related to new combination chemotherapy regimens. Hybrid physiologically-based (PB)-PK/PD models can rationally select promising combination protocols that will undergo phase I clinical evaluation in newly diagnosed patients using local and national resources in collaboration with the Gynecologic Oncology Group. PK/PD measurement inpatients will be integrated in a population-based PK-PD modeling strategy to identify and account for patient variables. This will further refine the treatment regimen and facilitate the design of individualized drug regimens. Overall, it is proposed that through the quantitative nature of PK/PD models, identification of rational combination regimens with significant impact on ovarian cancer will be expedited.
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