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; infusion times; once-daily dosing regimen; pediatrics; population pharmacokinetics.

Figure 1

Simulated concentration-time profiles of busulfan after intravenous administration of (a) EMA based., and (b) FDA based, once-daily dosing regimens with various infusion times. Dashed and dotted lines represent the 5th and 95th percentiles, respectively, and solid lines represent the median of the simulated concentration data. Horizontal dashed lines represent the reference values for maximum concentration.

Figure 2

Predictions of (a–d) daily and (e) total AUCs of busulfan during 4 dosing days according to various busulfan dosing regimens. The regimens were derived from EMA,, FDA,, Lee et al, Buffery et al, Yin et al, and Rhee et al. Shaded areas represent the therapeutic AUC ranges; on the total AUC plot, the wide range is 59,200–98,400 μg·h/L and the narrow range is 70,800–87,400 μg·h/L. The shaded ranges on the daily AUC plots are one quarter of the ranges on the total AUC plot (ie, 14,800–24,600 and 17,700–21,850 for wide and narrow range, respectively).

Figure 3

Percentages of patients achieving Cmax, all within reference values of (a) 1880 μg/L and (b) 3348 μg/L according to various infusion times. The dosing regimens were derived from EMA,, FDA,, Lee et al, Buffery et al, Yin et al, and Rhee et al. Cmax, all, maximum concentration of busulfan during 4 dosing days.