Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report.
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.
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
J M
JM
Reid
T W
TW
Pendergrass
M D
MD
Krailo
G D
GD
Hammond
M M
MM
Ames
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D004341:Drug Evaluation; D006801:Humans; D015255:Idarubicin / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007223:Infant; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*
C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin