title: IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies.
abstract: We currently calculate area under the busulfan concentration time curve (AUC) using 7 plasma busulfan concentrations (AUC7) drawn after the first of 16 i.v. busulfan doses given as a 2-hour infusion every 6 hours. The aim of this study was to develop and validate limited sampling strategies (LSSs) using 3 or fewer busulfan concentration values with which to reliably calculate AUC in children undergoing hematopoietic stem cell transplant (HSCT). Children in the development group (44) received i.v. busulfan at Sick Kids; the validation group consisted of 35 children who received care at CHU Ste-Justine. Busulfan doses given and subsequent plasma busulfan concentrations were recorded. LSSs using 1 to 3 concentration-time points were developed using multiple linear regression. LSS were considered to be acceptable when adjusted r(2) > 0.9, mean bias <15% and precision <15%. Extent of agreement between the AUC7 values and the LSS AUC was assessed by the intraclass correlation coefficient (ICC) and Bland-Altman (BA) analysis. Agreement was considered to be excellent when the lower limit of the 95% confidence limit of the ICC exceeded 0.9 and when the limits of agreement in the BA analysis were +/-15% for both AUC and dose. Administration of the theoretic adjusted busulfan doses based on each LSS was simulated and cases where the resulting AUC was >1500 or <900 microM x min were noted. LSSs using 1, 2, or 3 plasma busulfan concentrations were developed that showed excellent agreement with AUC7 and adjusted busulfan doses. In the validation sample, only the 2- and 3-point LSSs demonstrated acceptable precision and lack of bias. LSSs using 2 or 3 plasma busulfan concentrations can be used to reliably estimate busulfan AUC after IV administration in children undergoing HSCT.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. lee.dupuis@sickkids.ca
authors.forename: L Lee
authors.initials: LL
authors.lastname: Dupuis
authors.forename: Cathryn
authors.initials: C
authors.lastname: Sibbald
authors.forename: Tal
authors.initials: T
authors.lastname: Schechter
authors.forename: Marc
authors.initials: M
authors.lastname: Ansari
authors.forename: Adam
authors.initials: A
authors.lastname: Gassas
authors.forename: Yves
authors.initials: Y
authors.lastname: Théorêt
authors.forename: Nastya
authors.initials: N
authors.lastname: Kassir
authors.forename: Martin A
authors.initials: MA
authors.lastname: Champagne
authors.forename: John
authors.initials: J
authors.lastname: Doyle
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D016014:Linear Models; D018401:Sample Size
chemical_list: D002066:Busulfan