Population Pharmacokinetics of Busulfan in Pediatric Patients: Optimization of a Four-Times-Daily Dosing Regimen Based on EBMT Recommendations.

Background: The European Society for Blood and Marrow Transplantation (EBMT) recommends a busulfan target cumulative area under the curve (cAUC) of 78-101 mg·h/L for hematopoietic stem cell transplantation (HSCT). Currently, no population pharmacokinetic (PopPK)-optimized four-times-daily (Q6H) regimen reliably achieves this range. We developed a PopPK-guided dosing protocol to address this gap.

Methods: Clinical and demographic data from pediatric HSCT recipients receiving busulfan were retrospectively analyzed to develop a PopPK model. Bayesian estimation identified the optimal busulfan dose (0.50-1.25 mg/kg/dose) for target attainment in pediatric patients (age 0.5-18 years; weight 5-80 kg). Finally, the proposed dosing strategy was validated using an independent retrospective cohort.

Results: The PopPK model was developed using data from 65 pediatric patients. Age and bodyweight were identified as significant covariates. Optimized dosing recommendations for the Q6H × 4 days busulfan regimen were established through Bayesian estimation. For validation, two cohorts were retrospectively analyzed: (i) weight-based dosing (n = 19), and (ii) model-informed dosing (n = 15). The groups demonstrated comparable distributions in both age (p = 0.78) and weight (p = 0.63). Notably, the model-informed group achieved significantly higher cAUC values (mean difference, 18.0 mg·h/L; 95% confidence interval: 9.83-26.1 mg·h/L; p < 0.001), with 67% of these patients reaching the target exposure range.

Conclusion: We developed a Q6H × 4 days busulfan dosing regimen through PopPK modeling. For a representative 6-year-old patient with a bodyweight of 20 kg, the recommended dose is 1.25 mg/kg/dose. Therapeutic drug monitoring following the initial dose remains clinically essential.