Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

• Published in: Therapeutic drug monitoring Vol. 38; no. 3; p. 332
• Main Authors: Neely, Michael, Philippe, Michael, Rushing, Teresa, Fu, Xiaowei, van Guilder, Michael, Bayard, David, Schumitzky, Alan, Bleyzac, Nathalie, Goutelle, Sylvain
• Format: Journal Article
• Language: English
• Published: United States 01.06.2016
• Subjects: Administration, Intravenous; Adolescent; Algorithms; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - pharmacokinetics; Area Under Curve; Bayes Theorem; Bias; Busulfan - administration & dosage; Busulfan - pharmacokinetics; Child; Child, Preschool; Dose-Response Relationship, Drug; Humans; Infant; Models, Biological; Software; Young Adult
• ISSN: 1536-3694
• DOI: 10.1097/FTD.0000000000000276

Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4-9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden. The authors developed a nonparametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded manner, they compared dosage adjustments using the model in the BestDose software to dosage adjustments calculated by noncompartmental estimation of area under the time-concentration curve at a national reference laboratory in a cohort of patients not included in model building. Mean (range) age of the 53 model-building subjects was 7.8 years (0.2-19.0 years) and weight was 26.5 kg (5.6-78.0 kg), similar to nearly 120 validation subjects. There were 16.7 samples (6-26 samples) per subject to build the model. The BestDose cohort was also diverse: 10.2 years (0.25-18 years) and 46.4 kg (5.2-110.9 kg). Mean bias and imprecision of the 1-compartment model-predicted busulfan concentrations were 0.42% and 9.2%, and were similar in the validation cohorts. Initial dosages to achieve average concentrations of 600-900 ng/mL were 1.1 mg/kg (≤12 kg, 67% in the target range) and 1.0 mg/kg (>12 kg, 76% in the target range). Using all 9 concentrations after dose 1 in the Bayesian estimation of dose requirements, the mean (95% confidence interval) bias of BestDose calculations for the third dose was 0.2% (-2.4% to 2.9%, P = 0.85), compared with the standard noncompartmental method based on 9 concentrations. With 1 optimally timed concentration 15 minutes after the infusion (calculated with the authors' novel MMopt algorithm) bias was -9.2% (-16.7% to -1.5%, P = 0.02). With 2 concentrations at 15 minutes and 4 hours bias was only 1.9% (-0.3% to 4.2%, P = 0.08). BestDose accurately calculates busulfan intravenous dosage requirements to achieve target plasma exposures in children up to 18 years of age and 110 kg using only 2 blood samples per adjustment compared with 6-9 samples for standard noncompartmental dose calculations.