title: Effect of weight and maturation on busulfan clearance in infants and small children undergoing hematopoietic cell transplantation.
abstract: Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.
authors.affiliation: Department of Bioengineering and Therapeutics, University of California San Francisco, San Francisco, California.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.forename: Sung-Yun
authors.initials: SY
authors.lastname: Pai
authors.forename: Luis
authors.initials: L
authors.lastname: Pereira
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Rob F
authors.initials: RF
authors.lastname: Wynn
authors.forename: Geoff D E
authors.initials: GD
authors.lastname: Cuvelier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Mary A
authors.initials: MA
authors.lastname: Slatter
authors.forename: Janel
authors.initials: J
authors.lastname: Long-Boyle
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002066:Busulfan / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous / Q000379:methods*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan
keywords: Busulfan; Hematopoietic cell transplantation; Pediatrics; Pharmacokinetics
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