Pharmacokinetics of Mitoxantrone in Man and Laboratory Animals

Mitoxantrone (NOVANTRONE), an anthracenedione, is a novel anticancer agent with a wide spectrum of antitumor activity. Its anticancer activity is comparable to that of doxorubicin but with apparently significantly reduced cardiotoxicity. The recommended dosage regimen for the treatment of breast carcinoma is 12-14 mg/m2 given intravenously once every 21 days. Intravenously administered mitoxantrone disappears from the plasma of man and laboratory animals with multiexponential kinetics and with the terminal half-life ranging from 38 h to several days. It is rapidly cleared from the plasma by extensive sequestration into the tissues of the rat, dog, monkey, and man. However, redistribution back into the plasma and elimination from the body are slow processes. In both animals and man it is metabolized to the mono- and dicarboxylic acid derivatives, as well as glucuronide conjugates of these acids. Following intravenous administration, it is unchanged mitoxantrone that binds to most tissues. Rats, dogs, monkeys, and man, all eliminate mitoxantrone and its metabolites slowly by both renal and biliary excretion, with the biliary route predominating.