A population pharmacokinetic study of intravenous busulfan in pediatric patients undergoing hematopoietic stem cell transplantation

Abstract

Introduction: The dosage for once-daily intravenous busulfan in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) has been challenging mainly due to the high inter-individual variability of busulfan. This study was conducted to characterize the pharmacokinetics (PK) and identify significant covariates for intravenous (IV) busulfan, and to derive an optimal once-daily IV busulfan dosing nomogram for pediatric patients undergoing HSCT. Methods: A population PK analysis was performed using 2,183 busulfan concentrations in 137 pediatric patients (age: 0.6 - 22.2 years), who received IV busulfan once-daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once-daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration-time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once-daily regimen without therapeutic drug monitoring (TDM). Results: A one-compartment open linear PK model incorporating patients body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration–time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. Conclusions: The once-daily busulfan dosing nomogram suggested in this study performed better than the other regimens in achieving the therapeutic target AUC, which can be useful for clinicians, particularly in a setting where TDM service is not readily available.