Clinical pharmacokinetics of idarubicin.

Idarubicin (4-demethoxy-daunorubicin) is a new commercially available anthracycline antibiotic which is more active than daunorubicin, the accepted reference drug, in the treatment of acute myelogenous leukaemia, which generally involves the combination of an anthracycline and cytarabine [corrected]. It is characterised by metabolic transformation into a 13-dihydro derivative, idarubicinol, which is as active as the parent drug in in vitro models. The pharmacokinetics of idarubicin follow a 2- or 3-compartment plasma disappearance with half-life (t1/2) values of 13 min, 2.4h and 16h, clearance approximately 60 L/h/m2 and volume of distribution at steady-state of 1,500 L/m2. Idarubicinol is characterised by a very long elimination t1/2 of 55h. The ratio of metabolite: parent drug area under the plasma concentration-time curve is often > 2 and is even higher after 2 or 3 daily injections of the drug, the normal drug protocol used in induction or consolidation treatments of acute leukaemias. Idarubicin can also be administered orally and the pharmacokinetics are similar to those after intravenous administration, except that the idarubicinol: idarubicin ratio is increased, probably due to a liver first-pass effect. The bioavailability of idarubicin is 20 to 25%, but if the activity of idarubicinol is taken into account, it is effectively about 40%. After idarubicin administration by either route, there is a progressive accumulation of idarubicinol after multiple once-daily but not after once-weekly doses. About 10% of the injected dose is recovered in urine as idarubicin and idarubicinol, and only slightly higher proportions are recovered in bile. This suggests that other unidentified metabolites must be excreted by either or by both pathways.