PHARMACOKINETICS & TISSUE PENETRATION OF MMC IN PATIENTS

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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.