title: Comparison of algorithms for oral busulphan area under the concentration-time curve limited sampling estimate.
abstract: OBJECTIVE
  Therapeutic drug monitoring (TDM) of the first dose of busulphan during conditioning prior to allogeneic stem cell transplantation provides the possibility of improving the clinical outcome via dose adjustment of subsequent doses. The plasma area under the concentration-time curve (AUC) for busulphan is generally accepted as the parameter that gives the best exposure estimate; however, the sampling frequency needed for reliable AUC calculation remains controversial. The aim of the present investigation was to develop and evaluate a limited sampling model for oral busulphan.
  
  
  METHODS
  We have compared models using three to four samples with standard WinNonlin(®) adaptive compartment modeling based on eight samples as reference. The evaluated study population included both adult and pediatric patients, but the linear model was devised using analysis of only pediatric patient plasma concentrations. The present model was developed using data from 23 patients with a mean age of 38 years (range 13-59 years) and was evaluated in 20 pediatric patients with a mean age of 6 years (range 0.1-13 years) as well as 23 adult patients (mean age 43 years; range 18-67 years).
  
  
  RESULTS
  In 23 patients, the mean AUC from a curve fitting model (Purves method) and a single compartment model had an intraclass correlation coefficient (ICC) of 0.947. From a log-log plot of AUC values it was evident that using this estimate of the AUC would affect dose adjustment decisions for very few of the patients. Applying the linear model using three samples resulted in an ICC of 0.932, mostly due to worse performance in the adult population.
  
  
  CONCLUSIONS
  The present results support the use of limited sampling in clinical TDM for oral busulphan provided adequate algorithms and sampling times are used. Moreover, they also demonstrate the caution that is needed when transferring a pharmacokinetic model from a pediatric population to an adult population.
authors.affiliation: Department of Laboratory Medicine, Experimental Cancer Medicine, Karolinska Institutet Huddinge, Novum, 141 86, Stockholm, Sweden, fredrik.sjoo@capiostgoran.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Sjöö
authors.forename: Ibrahim
authors.initials: I
authors.lastname: El-Serafi
authors.forename: Jon
authors.initials: J
authors.lastname: Enestig
authors.forename: Jonas
authors.initials: J
authors.lastname: Mattsson
authors.forename: Johan
authors.initials: J
authors.lastname: Liwing
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D007223:Infant; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D002066:Busulfan