title: Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes.
abstract: We studied the pharmacokinetics and clinical outcome of a new once-daily intravenous area under the curve-targeted dosing scheme for busulfan based on body surface area. Eighteen children undergoing busulfan-based conditioning for allogeneic stem cell transplantation were enrolled. The age of the children ranged from 0.5 to 16 years. For all children, the starting dose was 80 mg/m. Unlimited dose adjustment was allowed to reach the target area under the curve (3800 micromol/l . min). This target area under the curve was determined on the basis of a previous study in our hospital. Pharmacokinetic studies were performed after the first dose. The median area under the curve on day 1 was 2616 (range 1781-5040) micromol/l . min at a dose of 80 mg/m. This resulted in a median dose increment to 114 (range 62-168) mg/m to reach the target area under the curve. In only one patient, the dose was decreased. Donor engraftment was established in 14 out of 18 patients (78%). Two of the four patients were successfully retransplanted. Relapse occurred in two patients (one died, one received additional treatment). Fourteen patients survived with a median follow-up of 1.6 years (1.0-2.2 years). The disease-free survival was 66% (12 of 18 patients). Despite the high systemic peak levels, there was no new unexpected or unusual toxicity. Moderate veno-occlusive disease was seen in one patient only. We conclude that intravenous busulfan in children administered once daily is safe, convenient and feasible, and can be dosed surface-based, independent of age. There was very limited (liver) toxicity, but the rejection rate was relative high, which can be probably overcome by a higher exposure to busulfan. Future investigations should be aimed at further optimizing the target area under the curve of intravenous busulfan for specific patient groups.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. J.Zwaveling@lumc.nl
authors.forename: Juliette
authors.initials: J
authors.lastname: Zwaveling
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Robbert G
authors.initials: RG
authors.lastname: Bredius
authors.forename: Robbert G
authors.initials: RG
authors.lastname: Maarten Bredius
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D018183:Transplantation Chimera
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan