title: Intravenous busulfan dose individualization - impact of modeling approach on dose recommendation.
abstract: TDM is intended to limit unintended consequences of drugs with narrow therapeutic indices. However, the application of different sampling strategies and pharmacokinetic approaches results in different dosing recommendations and ostensibly different outcomes. TDM approaches for intravenous busulfan dose individualization employ compartmental or non-compartmental modeling with anywhere from three to seven drug levels. This investigation was designed to examine the differences in dosing recommendations that arise in children (n = 30) when five different TDM approaches were employed. Significant differences in recommended doses between modeling strategies were observed. More importantly, the recommendations were discordant in 13 cases with at least one model recommending a dose adjustment in the opposite direction relative to the remaining models. The mathematical differences introduced by the application of different TDM approaches are not purely academic. Unification of busulfan TDM approaches should be considered to mitigate inconsistently applied dose adjustment, and facilitate comparisons of outcome, between clinical centers.
authors: Department of Clinical Pharmacology, Children's Mercy, Kansas City, MO, USA.|Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
authors: Susan M
authors: SM
authors: Abdel-Rahman
authors: Department of Pharmacy, Children's Mercy, Kansas City, MO, USA.
authors: K Leigh
authors: KL
authors: Casey
authors: Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.|Department of Clinical Chemistry, Children's Mercy, Kansas City, MO, USA.
authors: Uttam
authors: U
authors: Garg
authors: Department of Bone Marrow Transplantation, Children's Mercy, Kansas City, MO, USA.
authors: Jignesh
authors: J
authors: Dalal
mesh_terms: D019540:Area Under Curve; D016477:Artifacts; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007262:Infusions, Intravenous; D008962:Models, Theoretical; D010599:Pharmacokinetics; D012189:Retrospective Studies; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D002066:Busulfan
keywords: Food and Drug Administration; hematopoietic stem cell transplant; reference laboratory; therapeutic drug monitoring