Optimization of busulfan dosing regimen in pediatric patients using
population pharmacokinetic model incorporating GST polymorphisms
Abstract
Aim: The aim of this study was to develop a population pharmacokinetic
(PPK) model in Chinese children for intravenous busulfan, and to develop
a novel busulfan dosing regimen to support better area under the
concentration-time curve (AUC) targeting. Methods: We collected busulfan
concentration-time samples from 69 children who received intravenous
busulfan prior to allogeneic hematopoietic stem cell transplantation
(allo-HSCT). A population pharmacokinetic model for busulfan was
developed by nonlinear mixed effect modelling and was validated by an
external dataset (n=14). A novel busulfan dosing regimen was developed
through simulation on 1000 patients. Limited Sampling Strategy (LSS) was
established by the Bayesian forecasting. Absolute Prediction Error
(APE), Mean Absolute Prediction Error (MAPE) and relative Root Mean
Squared Error (rRMSE) were calculated to evaluate predictive accuracy.
Results: A one-compartment model with first-order elimination best
described the data. GSTA1 genotypes, BSA and AST were found to be
significant covariates of Bu clearance, and BSA had remarkable impact of
the volume. Moreover, recommended dose regimens for children with
different GSTA1 genotypes and BSA were developed with a perfect AUC
targeting. A two-point LSS, two hours and four hours after dosing,
behaved well with acceptable prediction precision. Conclusion: This
study developed a PPK model for busulfan that firstly incorporated GSTA1
genotypes in an Asian pediatric population. We recommend a BSA-based
dosing for personalizing busulfan therapy in pediatric population.
Additionally, an optimal LSS (C2h and C4h) provides convenience for
therapeutic drug monitoring (TDM) in the future.