title: Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing.
abstract: OBJECTIVE
  We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data.
  
  
  METHODS
  PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation).
  
  
  RESULTS
  The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]=target AUC[mg×h/L]×3.04L/h×(ABW/16.1)0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients.
  
  
  CONCLUSIONS
  We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.
authors.affiliation: Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, Corrensstr. 48, 48149, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Diestelhorst
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
mesh_terms: D000293:Adolescent; D000367:Age Factors; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001830:Body Surface Area; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D054796:Drug Dosage Calculations; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008954:Models, Biological; D049451:Nomograms; D017711:Nonlinear Dynamics; D015203:Reproducibility of Results
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan