Disposition of mitoxantrone in cancer patients

Abstract

We have used a highly sensitive high-performance liquid chromatographic assay to evaluate the pharmacokinetics and tissue disposition of mitoxantrone, an investigational anthracene derivative which has shown significant activity during Phase II clinical trials in the treatment of metastatic breast cancer, unfavorable histology non-Hodgkin's lymphoma, and acute leukemia. Mitoxantrone (12 mg/sq m over 30 to 35 min in 250 ml of dextrose 5% in water) and 14C-labeled mitoxantrone (specific activity, 8.85 muCi/mg) were administered to eight patients who had advanced soft tissue cancers. The plasma disappearance of mitoxantrone concentrations measured by high-performance liquid chromatography was best described by a three-compartment model with a mean t alpha of 0.1 h, a t beta of 1.1 h, and a t gamma of 42.6 h. The mean apparent Vc was 12.2 liters/sq m, while the mean Vd was 1875 liters/sq m. The mean plasma clearance was 0.57 liters/min/sq m, and the mean renal clearance was 45 ml/min/sq m. Only 6.5% of the total mitoxantrone dose was excreted in the urine as unchanged drug over 5 days. The mean recovery of 14C-labeled material in feces over 5 days was 18.3% of the administered dose. Thirty-five days after mitoxantrone administration to a patient who died of progressive kidney cancer, approximately 15% of the 14C dose could be accounted for in seven major organs. We conclude that mitoxantrone appears to distribute into a deep tissue compartment from which it is slowly released. These data provide a pharmacological rationale for use of mitoxantrone on an intermittent dosing schedule.