Idarubicin (4-demethoxydaunomycin) is an
anthracycline analogue with striking in vitro and in vivo activity against murine
leukemias. Based on activity in adults with
acute lymphoblastic leukemia, the Childrens
Cancer Study Group initiated studies to evaluate
idarubicin in children with
leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of
idarubicin and the major circulating metabolite
idarubicinol in 21 patients.
Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in
idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively.
Idarubicinol elimination was prolonged compared to that of the parent
drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of
idarubicin and
idarubicinol after a single dose of
idarubicin were 2.4 and 10.1%, respectively.
Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast,
idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.