Pharmacokinetic models to design & optimize clinical trials in ovarian cancer

（申请人描述）晚期卵巢癌妇女的化疗取得了良好的初步效果，但对长期疾病结局的影响有限，因为超过80%的这些患者最终会出现复发性疾病，并伴有耐药肿瘤的逐渐增加。通过开发新的化疗方案，特别是结合具有药理协同作用的药物，可以改善长期预后。这些新方案的毒性是巨大的，因此血液毒性的管理在临床试验设计中占据主导地位，没有直接或间接的证据表明期望的生物靶点实际上在肿瘤内被调节。潜在组合和序列的数量令人望而生畏，许多有希望的方案将被忽视，使用传统的经验方法进行临床试验设计。本应用的总体目标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。我们建议利用同基因大鼠晚期上皮性卵巢癌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。基于生理的(PB)-PK/PD混合模型可以合理选择有前景的联合方案，与妇科肿瘤组合作，利用地方和国家资源对新诊断患者进行I期临床评估。住院患者的PK/PD测量将整合到基于人群的PK-PD建模策略中，以识别和解释患者变量。这将进一步完善治疗方案，促进个体化药物方案的设计。综上所述，通过PK/PD模型的定量性质，可以加快寻找对卵巢癌有显著影响的合理联合用药方案。

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.