Pharmacokinetics of mitoxantrone in humans following single-agent infusion or intra-arterial injection therapy or combined-agent infusion therapy

Abstract

This study describes the pharmacokinetics of mitoxantrone determined by a sensitive and specific HPLC-method. The time-concentration curves of i.v.-treated patients (15 mg/m2 over 30 min) correspond to a three-compartment model with a T1/2 alpha of 12 min, a T1/2 beta of 93 min, and a slow elimination phase of 36 h. The central compartment volume was 26.22 and the distribution volume, 1381.9. The mean urinary excretion was 4.9% of the total dose. The pharmacokinetic parameters were also defined in five patients who were treated with combination chemotherapy (mitoxantrone 12 mg/m2, methotrexate 30 mg/m2 and vincristine 2 mg). These results were not different from those with the single-drug treatment, except for the volume of the central compartment, which was significantly decreased. The peak levels after hepatic arterial infusion of mitoxantrone were three times lower than those after the identical dose given i.v. to the same patient. Pleural fluid sampling showed a six-fold increase compared with the plasma level (12 ng/ml versus 2 ng/ml). A multiple linear regression analysis of the data revealed correlations between the pharmacokinetic results and some of the baseline parameters. It is possible to predict changes in the kinetic behaviour of mitoxantrone on the basis of these relations but on the other hand toxicity is less predictable from the baseline parameters or from the pharmacokinetic results.