title: Plasma pharmacokinetics of idarubicin and its 13-dihydro metabolite--a comparison of bolus versus 2 h infusion during a 3 day course.
abstract: The plasma pharmacokinetics of a second generation anthracycline derivative, idarubicin (Ida), have been studied in 17 patients with acute myelocytic leukemia (AML) and high risk features. The drug (10 mg/m2) was given in a randomized cross-over design as 3 min and 2 h infusions for three consecutive days. Cytosine arabinoside (Ara-C, 1 g/m2) was given on days 1-4. The plasma concentration time course of Ida was most properly described by the three-compartment pharmacokinetic model, independent of administration time. The maximum plasma concentration (Cmax) of Ida was reduced by a factor of 3 by increasing the infusion time from 3 min to 2 h. The pharmacokinetic pattern of the active metabolite idarubicinol (IdaOH) was only to a minor extent affected by the longer infusion time. The time course of IdaOH following each dose of Ida was accurately described by the one-compartment model with a first-order formation phase. The are under the plasma concentration versus time curves (AUC) of Ida and IdaOH were not affected by the administration time. Following Ida in combination with Ara-C, the medial duration of leukopenia (< 1.0 x 10(9)/l) was 14 days (range 5-56) and of thrombocytopenia (< 50 x 10(9)/l) was 22 days (range 7-120). The large majority of patients developed infectious complications. Two patients with MDS-AML showed a good response. The results of the present study give no evidence of reduced hematologic toxicity by increasing the administration time of Ida from 3 min to 2 h. However, minimizing Cmax, by administration of Ida as prolonged infusion during a 3 day course, might be clinically important in order to reduce cardiotoxicity and hopefully to increase anti-tumor efficacy through an increased accumulation of Ida and IdaOH in leukemic cells.
authors.affiliation: Department of Medicine, Karolinska Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Eksborg
authors.forename: M
authors.initials: M
authors.lastname: Björkholm
authors.forename: R
authors.initials: R
authors.lastname: Hast
authors.forename: E
authors.initials: E
authors.lastname: Fagerlund
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013050:Spectrometry, Fluorescence
chemical_list: D000903:Antibiotics, Antineoplastic; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin