An analysis of busulfan (Bu) pharmacokinetics revealed covariates associated with Bu clearance in a study of pediatric patients receiving busulfan prior to hematopoietic stem cell transplantation (HSCT). The analysis also resulted in an algorithm for individualizing first Bu doses in pediatric patients. The study and its outcomes were reported in the journal CPT: Pharmacometrics & Systems Pharmacology.

The multicenter study made use of data from 2 prospective, observational cohort studies (ClinicalTrials.gov Identifier: NCT01257854; Australian New Zealand Clinical Trial Registry Identifier: ACTRN12612000544875). The researchers performed a population pharmacokinetic analysis that included 402 pediatric patients given Bu with chemotherapy for conditioning prior to autologous or allogeneic HSCT.

For developing a model for individualized dosing, the researchers included information on patient and treatment characteristics, in addition to glutathione-s-transferase A1 (GSTA1) gene polymorphisms. Prior research had suggested these polymorphisms could influence Bu clearance in children during myeloablative conditioning.


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Data from a total of 302 patients were included in model development, and external model validation was performed with data from the remaining 100 patients. For analyses, there were 5293 Bu plasma concentrations and 994 busulfan pharmacokinetic profiles available across a range of dosing regimens.

Bu clearance was found to relate to body weight in an age-dependent manner. A few significant covariates were also found to affect Bu clearance. These included day 1 of Bu conditioning (versus other days), GSTA1 metabolic group as determined by gene polymorphism, and fludarabine coadministration. Fludarabine coadministration resulted in significantly lower clearance (-7%), and days following day 1 of Bu conditioning showed 9% lower clearance than on day 1. A total of 3 GSTA1 metabolic groups were identified based on GSTA1 gene polymorphisms, with group 1 showing 10% higher clearance than seen with group 2, and group 3 showing 12% lower clearance than group 2 did.

When the model developed in this study was applied to the external validation cohort, 81% of modeled cases had a predicted area under the curve for first-dose Bu clearance that was within the therapeutic window. The model also reportedly showed low bias (mean prediction error, -0.5%; 95% CI, -3.1-2.0). A metric of precision, the mean absolute prediction error percentage for the model was 18.7% (95% CI, 17.0-20.5) for predicting Bu clearance for dosing.

“The model resulted in a dose recommendation algorithm that could accurately predict Bu exposure in more than 80% of pediatric patients,” the researchers concluded in their report. Future research is planned to evaluate the feasibility of routine analysis of GSTA1 genotyping for Bu dose recommendations.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Ben Hassine K, Nava T, Théoret Y, et al. Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: results from a multicenter population pharmacokinetic study. CPT Pharmacometrics Syst Pharmacol. 2021;10(9):1043-1056. doi:10.1002/psp4.12683