PHARMACOKINETICS & TISSUE PENETRATION OF MMC IN PATIENTS

该应用程序是三个交互式研究项目之一。 我们 建议检查药代动力学和组织渗透 丝裂霉素C（MMC）在浅表性膀胱癌患者中的应用 膀胱灌注MMC的疗效试验。 两种治疗方案，即 基于经验的标准方案和我们基于药理学的优化方案 方案进行了比较。 在标准治疗对照组中，患者 将根据一般临床实践接受MMC。 优化 治疗方案是增强肿瘤对MMC的暴露，并最小化 患者间差异。 根据我们之前的研究结果， 膀胱灌注MMC在尿液和膀胱壁中的药代动力学，以及我们的 建立了药代动力学模型，我们使用计算机模拟， 预测肿瘤部位的MMC浓度。 这些信息， 结合我们关于抑制细胞增殖所需的MMC浓度的数据， 50%或90%的患者肿瘤增殖被用来预测 治疗效果 这些预测表明， 的膀胱肿瘤可以减少约22%，使用优化的 方案. 该应用程序有四个独立和互动的目标。(a)的 将研究药代动力学以确定所需药物 在优化治疗组中达到的浓度， 优化和标准治疗组的药代动力学。(b)一 临床试验的第二个目的是将治疗 个体患者的结果与药理学数据。 三通 比较靶部位的药物浓度、药物诱导的 抗肿瘤作用和治疗结果将允许评估 常用的体外药效学关系 终点，即肿瘤细胞DNA合成的抑制，患者 反应(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 建议研究接受预防性治疗的患者的剂量依赖性 根治性化疗之前。(d)我们已经证明， 尿路上皮层是药物渗透的主要屏障， 组织，并且药物不能穿透深层组织可能 部分原因是侵袭性肿瘤对 膀胱内治疗 渗透促进剂对膀胱的影响 壁MMC浓度将被确定，以检查其潜力 临床应用于治疗肌肉侵犯性肿瘤。

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.