title: Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning.
abstract: Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 μM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 μM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children improves the performance of most guidelines. Regardless of the guideline used, therapeutic drug monitoring is essential to verify achievement of the target AUC.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jamie H
authors.initials: JH
authors.lastname: Zao
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tal
authors.initials: T
authors.lastname: Schechter
authors.affiliation: Department of Pharmacy, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Wenchao Jessica
authors.initials: WJ
authors.lastname: Liu
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gerges
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Gassas
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.affiliation: Division of Immunology & Allergy, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Eyal
authors.initials: E
authors.lastname: Grunebaum
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada; Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: lee.dupuis@sickkids.ca.
authors.forename: L Lee
authors.initials: LL
authors.lastname: Dupuis
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan
keywords: Busulfan; Dosing; Pediatrics; Pharmacokinetics