PHARMACOKINETICS & TISSUE PENETRATION OF MMC IN PATIENTS

药代动力学

• 批准号: 2099600
• 负责人: M GUILLAUME WIENTJES
• 金额: $ 13.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099600
• 关键词: antineoplastic antibiotics; bladder neoplasm; clinical trials; computer simulation; dogs; dosage; drug metabolism; gene expression; human subject; human therapy evaluation; mitomycin C; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; prognosis

This application is one of three interactive research projects. We propose to examine the pharmacokinetics and tissue penetration of mitomycin C (MMC) in superficial bladder cancer patients enrolled in an efficacy trial of intravesical MMC. Two treatment regimens, i.e. the standard empirically based regimen and our pharmacology based optimized regimen are compared. In the standard treatment control arm, patients will receive MMC according to general clinical practice. The optimized treatment regimen is to enhance the tumor exposure to MMC and to minimize inter-intrapatient variability. Based on our previous results on the pharmacokinetics of intravesical MMC in urine and bladder wall, and our established pharmacokinetic models, we used computer simulations to project the MMC concentration at the tumor sites. This information, combined with our data on the MMC concentrations needed to inhibit cell proliferation in patient tumors by 50 or 90% was used to project the treatment effect. These projections suggest that the rate of recurrence of bladder tumors can be reduced by approximately 22% using the optimized regimen. This application has four independent and interactive aims. (a) The pharmacokinetics will be studied to ascertain that the desired drug concentrations are achieved in the optimized treatment arm and to compare the pharmacokinetics in the optimized and standard treatment arms. (b) A second objective of the clinical trial is to correlate the treatment outcome in individual patients with the pharmacologic data. A three-way comparison of the drug concentration at the target site, the drug-induced antitumor effect and the treatment outcome will permit the evaluation of the relationship between the commonly used in vitro pharmacodynamic endpoint, i.e. inhibition of tumor cell DNA synthesis, with patient response. (c) Our previous animal studies suggest a dose-dependent increase of bladder wall concentrations after intravesical treatment. We propose to study the dose dependency in patients who receive prophylactic chemotherapy prior to radical cystectomy. (d) We have shown that the urothelial layer is the major barrier to drug penetration in the deeper tissue, and that the inability of drug to penetrate the deep tissues may be in part responsible for the poor response of invasive tumors to intravesical therapy. The effect of penetration enhancers on bladder wall MMC concentrations will be determined to examine their potential clinical application for the treatment of muscle invading tumors.

这个应用程序是三个互动研究项目之一。我们 建议研究阿司匹林的药代动力学和组织渗透 丝裂霉素C(MMC)治疗浅表性膀胱癌 丝裂霉素C膀胱内的疗效试验。两种治疗方案，即 基于经验的标准疗法和基于我们的药理学的优化 对治疗方案进行了比较。在标准治疗控制臂中，患者 将根据一般临床实践接受MMC。经过优化的 治疗方案是增加肿瘤对MMC的暴露，并将 患者内部的变异性。基于我们之前关于 丝裂霉素C在尿液和膀胱壁中的药代动力学 建立了药物动力学模型，我们使用计算机模拟来 将MMC浓度投射到肿瘤部位。这些信息， 结合我们关于抑制细胞所需MMC浓度的数据 患者肿瘤增殖50%或90%被用来预测 治疗效果。这些预测表明，复发率 使用优化的 养生法。 这个应用程序有四个独立和交互的目标。(A) 将对药物动力学进行研究，以确定所需药物 在优化的治疗臂中实现浓度并进行比较 优化治疗组和标准治疗组的药代动力学。(B)A类 临床试验的第二个目标是将治疗与 用药理学数据对个别患者的预后进行分析。三人行 靶部位药物浓度的比较，药物诱导 抗肿瘤效果和治疗结果将允许评估 常用的体外药效学指标与药效学的关系 终点，即抑制肿瘤细胞DNA合成，与患者 回应。(C)我们之前的动物研究表明， 膀胱内治疗后膀胱壁浓度增加。我们 建议研究接受避孕药的患者的剂量依赖性 根治性膀胱切除术前的化疗。(四)我们已证明 尿路上皮层是药物深层渗透的主要障碍 组织，而药物不能穿透深层组织可能 对侵袭性肿瘤的不良反应负有部分责任 膀胱内治疗。渗透促进剂对膀胱的影响 将确定壁上MMC的浓度以检查其潜力 肌肉侵袭性肿瘤的临床应用。