Population pharmacokinetics and model-informed precision dosing of busulfan in Chinese pediatric allogeneic hematopoietic stem cell transplantation: a prospective real-world cohort study

Background Busulfan is a cornerstone of conditioning regimens for pediatric allogeneic hematopoietic stem cell transplantation (HSCT), yet its narrow therapeutic index and high pharmacokinetic variability necessitate individualized dosing. This study aimed to develop and evaluate a population pharmacokinetic (PopPK) model for busulfan in Chinese pediatric allogeneic HSCT recipients, characterize the exposure-response relationship, and establish a model-informed precision dosing (MIPD) strategy for clinical implementation. Methods This prospective, single-center study was conducted at Children’s Hospital of Fudan University between August 2020 and January 2026. Plasma busulfan concentrations were quantified using a validated HPLC-MS/MS. PopPK analysis was performed using nonlinear mixed-effects modeling. The association between busulfan exposure (AUC 0–6h ) and clinical outcomes was evaluated using logistic regression. Monte Carlo simulations were performed to derive an age- and body weight-stratified dosing regimen, and a closed-loop MIPD workflow was developed for clinical implementation. Results A total of 290 pediatric HSCT recipients contributed 1543 busulfan concentration measurements. A two-compartment model with first-order elimination adequately characterized busulfan pharmacokinetics. Body weight and age were significant determinants of clearance. For a 70 kg reference individual, the population estimates of clearance and central volume of distribution were 12.4 L/h and 40.8 L, respectively. The model demonstrated good predictive performance in internal evaluation. Under empirical dosing, only 47.6% of patients achieved the target AUC 0–6h of 900–1350 μM min/L. Busulfan exposure (AUC 0–6h ) was not significantly associated with mortality (OR, 1.002; 95% CI, 1.000–1.004; P = 0.069) or acute graft-versus-host disease (OR, 1.001; 95% CI, 1.000–1.002; P = 0.161). Monte Carlo simulations supported an age- and body weight-stratified initial dosing regimen. A closed-loop MIPD workflow was established in which the initial dose is selected according to the simulated dosing regimen, followed by therapeutic drug monitoring and pharmacist-physician collaborative dose adjustment when AUC 0–6h falls outside the prespecified target range. Conclusion A PopPK model with body weight and age as key determinants of busulfan clearance was developed and evaluated in a large real-world cohort of Chinese pediatric allogeneic HSCT recipients. The proposed MIPD framework provides a practical approach for optimizing busulfan therapy in this population.