title: Toxicity and pharmacokinetics of i.v. busulfan in children before stem cell transplantation.
abstract: We have introduced a dimethylacetamide-based i.v. formulation of busulfan into pediatrics with a dose intensity [as measured by area under curve (AUC)] comparable to that achieved by oral busulfan while reducing variability. The target AUC was defined at 1600+/-600 microM.min. The children received 15 doses of i.v. busulfan as 2-h infusions with a dose calculated to be 80% of the oral dose according to the malignancy-related protocol. The first infusion was applied as a double dose over 4 h with the second infusion following 12 h thereafter. Plasma samples were analyzed for busulfan by a validated LC-MS method and toxicity was assessed at least up to day 100+ after transplantation. Nineteen children (median age: 4 years, range: 0.9-17.3) were included. The AUC after the first dose ranged from 570 to 1410 microM.min [geometric mean 1010 microM.min, coefficient of variation (CV)=22%, n=17]. In nine out of 17 patients, the AUC after the first dose was out of the target range. Two patients had neurotoxic symptoms, which were attributable to busulfan in one individual. No case of severe hepatic veno-occlusive disease or other serious toxic events occurred. We conclude that i.v. busulfan displays a smaller interpatient variability in exposure compared to oral busulfan (CV of 24% after i.v. versus CV of 37% after oral busulfan). The equivalent dose to 1 mg/kg oral busulfan with regard to the AUC appears to be higher than 0.8 mg/kg.
authors.affiliation: Universitätsklinikum Münster, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Münster, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Oechtering
authors.forename: Brunhild
authors.initials: B
authors.lastname: Schiltmeyer
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Gudrun
authors.initials: G
authors.lastname: Würthwein
authors.forename: Thomas
authors.initials: T
authors.lastname: Mürdter
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Josef
authors.initials: J
authors.lastname: Vormoor
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Gudrun
authors.initials: G
authors.lastname: Fleischack
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D033581:Stem Cell Transplantation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan