Pharmacokinetic models to design & optimize clinical trials in ovarian cancer

描述：(申请人描述)晚期卵巢癌患者的化疗最初取得了良好的效果，但对长期疾病结果的影响有限，因为超过80%的患者最终会出现复发，并伴有抗药性肿瘤的逐渐增加。通过开发新的化疗方案，特别是通过合并显示药理协同作用的药物，可能会改善长期结果。这些新方案的毒性很大，因此血液毒性的管理在临床试验设计中占据主导地位，而没有直接或间接的证据表明所需的生物靶点实际上在肿瘤内受到调节。在临床试验设计中，使用传统的经验性方法将忽略潜在组合和序列的数量，以及许多有希望的方案。这项应用的总体目标将是在临床前模型和临床试验中应用和整合药代动力学(PK)和药效学(PD)原理，以选择和优化卵巢癌患者的联合化疗。我们建议利用晚期卵巢上皮性癌的同基因大鼠模型作为翻译工具来解决与新的联合化疗方案相关的生物学问题。混合生理学(PB)-PK/PD模型可以合理地选择有前景的组合方案，这些方案将与妇科肿瘤组合作，利用当地和国家资源在新诊断的患者中进行I期临床评估。住院患者的PK/PD测量将被整合到基于人群的PK-PD建模策略中，以识别和考虑患者变量。这将进一步细化治疗方案，促进个性化用药方案的设计。总之，我们建议通过PK/PD模型的定量性质，加速寻找对卵巢癌有显著影响的合理联合方案。

DESCRIPTION: (Applicant's Description) 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.