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

Veronique Michaud,Philippe Bouchard,Martin Franco,Karine Alain,Benoit Pronovost,Jacques Turgeon,Sarah Bilodeau,François Bélanger,Barbara Vadnais,My Tran

doi:10.3390/pharmaceutics11090440

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.

Highlights

In current hematopoietic stem cell transplantation (HSCT) practices, busulfan is a commonly used alkylating agent
In this study, we demonstrated that the administration of an initial standard oral dose of busulfan (1 mg/kg of a 4 mg/kg/day regimen) to patients with a glutathione S-transferase alpha 1 (A1) (GSTA1)*B*B genotype was associated with higher plasma concentrations of busulfan and with lower estimated oral clearance of the drug
We demonstrated that the administration of an initial standard oral dose of busulfan (1 mg/kg of a 4 mg/kg/day regimen) to patients with a GSTA1*B*B genotype was associated with higher plasma concentrations of busulfan and with lower estimated oral clearance of the drug

Summary

Introduction

In current hematopoietic stem cell transplantation (HSCT) practices, busulfan is a commonly used alkylating agent. Current therapeutic monitoring methods of the drug involve taking numerous (often up to 10) blood samples to calculate patient’s plasma concentration vs time area under the curve (AUC) [4]. We and others have demonstrated the value of limited sampling strategies to estimate mean busulfan plasma concentration and compute required busulfan doses in these leukemic patients [5,6,7,8,9]. 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. 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. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies

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Methods

Results

Conclusion