title: Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children.
abstract: OBJECTIVE
  To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.
  
  
  METHODS
  The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.
  
  
  RESULTS
  CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.
  
  
  CONCLUSIONS
  We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment.
authors.affiliation: Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany. tramemirjam@uni-muenster.de
authors.forename: Mirjam N
authors.initials: MN
authors.lastname: Trame
authors.forename: Martin
authors.initials: M
authors.lastname: Bergstrand
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
mesh_terms: D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001830:Body Surface Area; D001835:Body Weight; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan