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

• Main Authors: Veronique Michaud, My Tran, Benoit Pronovost, Philippe Bouchard, Sarah Bilodeau, Karine Alain, Barbara Vadnais, Martin Franco, François Bélanger, Jacques Turgeon
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: Pharmaceutics
• Subjects: busulfan; glutathione S-transferase; genetic polymorphism; limited sampling strategy; pharmacokinetics
• Online Access: https://www.mdpi.com/1999-4923/11/9/440

Background: 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. Methods: 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 plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients&#8217; files and <i>GSTA1 *A</i> and <i>*B</i> allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. Results: Carriers of <i>GSTA1*B</i> exhibited lower busulfan CLo than patients with an <i>*A/*A</i> genotype (<i>p</i> &lt; 0.002): Busulfan CLo was 166 &#177; 31, 187 &#177; 37 vs. 207 &#177; 47 mL/min for <i>GSTA1*B/*B,</i> <i>*A/*B</i> and <i>*A/*A</i> 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 <i>GSTA1*A/*A</i>, 50% for <i>*A/*B,</i> and 65% for <i>*B/*B</i>. The LSMs correctly identified &#8805;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 <i>GSTA1</i> loss of function <i>*B</i> allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with <i>GSTA1</i> explain a significant part of busulfan CLo variability which could be captured by LSM strategies.