Busulfan dose Recommendation in Inherited Metabolic Disorders: Population Pharmacokinetic Analysis

Area of Science:

• Pharmacology and Therapeutics
• Oncology
• Pediatrics

Background:

• Busulfan is a key alkylating agent in hematopoietic cell transplantation (HCT) conditioning regimens.
• Population pharmacokinetic (popPK) models optimize busulfan exposure, improving event-free survival post-HCT.
• Previous popPK studies of busulfan were limited in patients with inherited metabolic disorders (IMD).

Purpose of the Study:

• To characterize the population pharmacokinetics (popPK) of busulfan in a large cohort of pediatric and young adult patients with IMD undergoing HCT.
• To develop and evaluate an optimized busulfan dosing regimen for IMD patients to improve target exposure attainment.

Main Methods:

• A popPK analysis was conducted on busulfan concentrations from 78 IMD patients receiving intravenous busulfan.
• A 1-compartment linear elimination model was utilized, identifying total body weight and time since infusion start as significant covariates.
• Individual doses were calculated to achieve a target cumulative area under the curve (cAUC) of 80-100 mg·h/L.

Main Results:

• The developed dosing regimen showed improved probabilities of achieving the target cAUC compared to conventional dosing: 47% vs. 43% (body weight <12 kg) and 48% vs. 36% (body weight ≥12 kg).
• Total body weight and time from busulfan infusion start were significant covariates affecting busulfan clearance.
• The study successfully characterized intravenous busulfan PK in a substantial IMD cohort.

Conclusions:

• The developed population pharmacokinetic model and proposed dosing regimen can enhance busulfan target cAUC attainment in IMD patients.
• Optimized busulfan dosing is critical for improving outcomes in HCT for inherited metabolic disorders.
• This research provides a foundation for personalized busulfan dosing in this vulnerable patient population.