title: Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children:  the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation.
abstract: BACKGROUND
  Intravenous (IV) busulfan (Bu) dosing approved in Europe based on 5 body weight (BW) strata has been validated for targeting Bu exposures in children undergoing hematopoietic stem-cell transplantation and with mostly malignant diseases. The authors conducted an observational study aiming to investigate the behavior and ontogeny of IV Bu pharmacokinetic (PK) disposition, and to reevaluate the consistency of the BW-based dosing in very young children with rare diseases.
  
  
  METHODS
  The observational study comprised 115 patients, mostly infants with immunodeficiencies and metabolic inherited disorders and with altered liver function and/or iron overload. Additional data (90 children, mostly malignant diseases) were pooled with the first data set. The overall data (205 children aged from 10 days to 15 years) were analyzed using population PK modeling.
  
  
  RESULTS
  The BW remained the main determinant of IV Bu PK, and no further covariate effect was identified. Bu clearance (CL) variability was best described by BW allometric functions. Increase of drug CL with the child's growth was faster in younger children. This pattern is likely related to the maturation of GSTA1 enzymes during infancy and was accounted for in the model by estimating a higher BW allometric exponent in children <9 kg compared with that in children ≥9 kg. IV Bu PK was not modified in children with altered liver function and/or iron overload, and no disease specific difference was observed. Bu dosing either adjusted according to the final model or with the approved EU labeling yields similar targeting performances. For both dosing strategies, the percent of patients achieving the therapeutic area under the curve window (900-1500 μmole·min/L were 60% and 70%-90% in children <9 and ≥9 kg, respectively.
  
  
  CONCLUSIONS
  A population PK model accounting for the highest Bu CL in the youngest patients was validated on training and evaluation data sets. The BW-based dosing strategy recommended in Europe proved to be consistent on a large paediatric cohort representative of the population heterogeneity observed in hematopoietic stem-cell transplantation.
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Dalle
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bleyzac
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Claire
authors.initials: C
authors.lastname: Galambrun
authors.forename: Véronique
authors.initials: V
authors.lastname: Kemmel
authors.forename: Zeinab D
authors.initials: ZD
authors.lastname: Abdi
authors.forename: Sophie
authors.initials: S
authors.lastname: Broutin
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pétain
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
mesh_terms: D000293:Adolescent; D000367:Age Factors; D019540:Area Under Curve; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008954:Models, Biological
chemical_list: D007166:Immunosuppressive Agents; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D002066:Busulfan