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Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

ABSTRACT: BACKGROUND:Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. METHODS:This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients' files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. RESULTS:Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ?91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. CONCLUSION:Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.

SUBMITTER: Michaud V

PROVIDER: S-EPMC6781287 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Impact of <i>GSTA1</i> Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

Michaud Veronique V Tran My M Pronovost Benoit B Bouchard Philippe P Bilodeau Sarah S Alain Karine K Vadnais Barbara B Franco Martin M Bélanger François F Turgeon Jacques J

Pharmaceutics 20190901 9

<h4>Background</h4>Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (<i>GSTA1</i>) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation.<h4>Methods</h4>This is a quasi-experimental retrospective study in adult patients (<i>n</i> = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plas ...[more]

PMID: 31480560

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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

Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

Publications

Impact of <i>GSTA1</i> Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

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