Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients

Abstract

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)