Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times

Abstract

Purpose

Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity.

Patients and methods

Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens.

Results

Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion.

Conclusion

While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

Keywords:

• busulfan
• pediatrics
• population pharmacokinetics
• once-daily dosing regimen
• infusion times

Data Sharing Statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

This research was supported by Wonkwang University in 2022.

Disclosure

The authors have no conflicts of interest to disclose in this work.