Pharmacokinetic models to design & optimize clinical trials in ovarian cancer

产品说明：晚期卵巢癌患者的化疗取得了良好的初步结果，对长期疾病结果的影响有限，因为超过80%的这些患者最终发展为复发性疾病，伴随着耐药肿瘤的逐渐增加。通过开发新的化疗方案，特别是通过合并表现出药理学协同作用的药物，可能会改善长期结局。 这些新方案的毒性是显著的，因此血液学毒性的管理在临床试验设计中占据主导地位，没有直接或间接证据表明所需的生物靶点实际上在肿瘤内被调节。 使用传统的经验性临床试验设计方法，潜在的组合和序列的数量令人生畏，许多承诺方案将被忽视。 本申请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。我们建议利用同系大鼠晚期上皮性卵巢癌模型作为一种翻译工具，以解决与新的联合化疗方案相关的生物学问题。 基于生理学的混合（PB）-PK/PD模型可以合理选择有前景的联合方案，这些方案将与妇科肿瘤组合作，使用当地和国家资源在新诊断患者中进行I期临床评价。将在基于人群的PK-PD建模策略中整合住院患者的PK/PD测量，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。 总体而言，建议通过PK/PD模型的定量性质，将加快确定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.