title: Predictive performance of a busulfan pharmacokinetic model in children and young adults.
abstract: BACKGROUND
  Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This study assesses the predictive performance of this busulfan PK model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices, from 5 international pediatric transplant centers.
  
  
  METHODS
  The previously published (original) busulfan PK model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent hematopoietic stem cell transplantation in 5 international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n = 158) and combined datasets (n = 403), and subpopulation analyses were evaluated.
  
  
  RESULTS
  The original busulfan PK model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the 5 external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices were adequately predicted.
  
  
  CONCLUSIONS
  Our pediatric busulfan PK model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age, or body mass index. This busulfan PK model forms the basis for individualized busulfan dosing.
authors.affiliation: Department of Clinical Pharmacy, University Medical Center, Utrecht, the Netherlands. i.h.bartelink@gmail.com
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Kesteren
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.forename: Geoff D E
authors.initials: GD
authors.lastname: Cuvelier
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.forename: Mary A
authors.initials: MA
authors.lastname: Slatter
authors.forename: Robert
authors.initials: R
authors.lastname: Chiesa
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D019540:Area Under Curve; D015992:Body Mass Index; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D011237:Predictive Value of Tests; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D002066:Busulfan