title: Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?
abstract: BACKGROUND
  A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses.
  
  
  METHODS
  Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized.
  
  
  RESULTS
  Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC₀₋₂₄.
  
  
  CONCLUSIONS
  Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.
authors.affiliation: *Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand; †Department of Medicine, University of Otago, Christchurch, New Zealand; and ‡Canterbury Health Laboratories, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Buffery
authors.forename: Kirstie M
authors.initials: KM
authors.lastname: Allen
authors.forename: Paul K L
authors.initials: PK
authors.lastname: Chin
authors.forename: Grant A
authors.initials: GA
authors.lastname: Moore
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Begg
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001800:Blood Specimen Collection; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008875:Middle Aged; D017711:Nonlinear Dynamics; D013997:Time Factors; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan