Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation

Abstract

Aims: The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism.

Methods: Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 μM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children.

Results: A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%).

Conclusion: This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.

Keywords: GSTA1; busulfan; children; polymorphisms; population pharmacokinetics; stem cell transplantation.

© 2018 The British Pharmacological Society.

Figures

Figure 1

Goodness‐of‐fit of the final model. (A) Observed individual concentrations of Bu vs. population predicted concentrations; (B) observed individual concentration of Bu vs. individual predicted concentration; (C) conditional weighted residuals vs. population predicted concentrations; (D) conditional weighted residuals vs. time after the first dose

Figure 2

Prediction‐corrected visual prediction check (pcVPC) of final model. Q6H for doses every 6 h and Q24H for doses every 24 h. The dots represent observed concentrations and dashed lines represent 2.5th, 50th and 97.5th percentiles of observed‐corrected concentrations; solid lines represent 2.5th, 50th and 97.5th simulated percentiles within each bin; shaded areas represent 95% confidence interval of the 2.5th, 50th and 97.5th prediction intervals