title: Development of a population pharmacokinetics-based sampling schedule to target daily intravenous busulfan for outpatient clinic administration.
abstract: Therapeutic drug monitoring of daily intravenous (IV) busulfan currently requires hospital admission. Population pharmacokinetic modeling and determination of an optimal pharmacokinetic sampling schedule over 6 hours could allow for personalizing these busulfan doses in the outpatient clinic. A retrospective evaluation of daily IV busulfan pharmacokinetics was conducted in 37 adults. SPK and NONMEM software were used to estimate the population pharmacokinetic parameters. Subsequent to model building, the area under the concentration-time curve (AUC) was computed using NONMEM. A 1-compartment model best fit the data. The optimal 6-hour outpatient sampling schedule was constructed using a simulation approach that sought to minimize scaled mean squared error for the clearance and volume parameters for each simulated individual. The best sampling times were 2.75, 3, 3.25, 5.5, 5.75, and 6 hours from the start of a 3-hour infusion. With these sampling times, the maximum a posteriori (MAP) Bayesian estimation was superior to maximum likelihood estimation with more samples. An individual patient's busulfan AUC and pharmacokinetic parameters may be accurately estimated with an outpatient sampling schedule that is used in conjunction with MAP Bayesian estimation, with a parameter prior based on population pharmacokinetic modeling. Prospective validation of this approach is needed.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195-7630, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Salinger
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
authors.forename: David K
authors.initials: DK
authors.lastname: Blough
authors.forename: Paul V
authors.initials: PV
authors.lastname: O'Donnell
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Pawlikowski
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
mesh_terms: D000328:Adult; D000368:Aged; D000554:Ambulatory Care Facilities; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan