Dataset Information

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 ?M 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.

SUBMITTER: Nava T

PROVIDER: S-EPMC6005620 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Nava Tiago T Kassir Nastya N Rezgui Mohamed Aziz MA Uppugunduri Chakradhara Rao Satyanarayana CRS Huezo-Diaz Curtis Patricia P Duval Michel M Théoret Yves Y Daudt Liane E LE Litalien Catherine C Ansari Marc M Krajinovic Maja M Bittencourt Henrique H

British journal of clinical pharmacology 20180427 7

<h4>Aims</h4>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.<h4>Methods</h4>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 v ...[more]

PMID: 29469189

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Project description:Objective: Busulfan (BU) is a bi-functional DNA-alkylating agent used in patients undergoing hematopoietic stem cell transplantation (HSCT). Over the last decades, several population pharmacokinetic (pop PK) models of BU have been established, but external evaluation has not been performed for almost all models. The purpose of the study was to evaluate the predictive performance of published pop PK models of intravenous BU in adults using an independent dataset from Chinese HSCT patients, and to identify the best model to guide personalized dosing. Methods: The external evaluation methods included prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. In prediction-based diagnostics, the relative prediction error (PE%) was calculated by comparing the population predicted concentration (PRED) with the observations. Simulation-based diagnostics included the prediction- and variability-corrected visual predictive check (pvcVPC) and the normalized prediction distribution error (NPDE). Bayesian forecasting was executed by giving prior one to four observations. The factors influencing the model predictability, including the impact of structural models, were assessed. Results: A total of 440 concentrations (110 patients) were obtained for analysis. Based on prediction-based diagnostics and Bayesian forecasting, preferable predictive performance was observed in the model developed by Huang et al. The median PE% was -1.44% which was closest to 0, and the maximum F20 of 57.27% and F30 of 72.73% were achieved. Bayesian forecasting demonstrated that prior concentrations remarkably improved the prediction precision and accuracy of all models, even with only one prior concentration. Conclusion: This is the first study to comprehensively evaluate published pop PK models of BU. The model built by Huang et al. had satisfactory predictive performance, which can be used to guide individualized dosage adjustment of BU in Chinese patients.

Dataset Information

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

Publications

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

Similar Datasets

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