Effect of <i>GSTA1</i> Variants on Busulfan-Based Conditioning Regimen Prior to Allogenic Hematopoietic Stem-Cell Transplantation in Pediatric Asians

• Main Authors: Ai-Hoc Nguyen (Author), Mohitosh Biswas (Author), Apichaya Puangpetch (Author), Santirhat Prommas (Author), Samart Pakakasama (Author), Usanarat Anurathapan (Author), Jiratha Rachanakul (Author), Rattanaporn Sukprasong (Author), Nutthan Nuntharadtanaphong (Author), Nutcha Jongjitsook (Author), Suradej Hongeng (Author), Chonlaphat Sukasem (Author)
• Format: Book
• Published: MDPI AG, 2022-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione <i>S</i>-transferase (GST) has strong evidence in Caucasians and some adult Asians but not in pediatric Asian patients. This study was aimed at investigating the associations of <i>GST</i> genetic polymorphisms with variations in the pharmacokinetic (PK) properties of busulfan in pediatric Asian patients. This retrospective cohort study recruited 92 pediatric patients. The polymorphism of <i>GSTA1</i> was genotyped by Sanger sequencing, and <i>GSTM1</i> and <i>GSTP1</i> were genotyped by real-time PCR. Drug concentration and PK estimation were identified using an LC-MS/MS method and a noncompartmental model. Statistical analysis was performed by R software. Out of 92 patients, 48 (53%) were males, the mean age was 8.4 ± 5.12 years old, and the average weight was 26.52 ± 14.75 kg. The allele frequencies of <i>GSTA1*B</i> and of <i>GSTM1</i> and <i>GSTP1</i>* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with <i>GSTA1*B</i> had a statistically significant impact on the PK of busulfan, whereas those with <i>GSTM1</i> and <i>GSTP1</i> did not (<i>p</i> > 0.05). The carriers of <i>GSTA1*B</i> showed a significant difference compared to noncarriers in terms of t_1/2 (for first dose: 161.9 vs. 134.3 min, <i>p</i> = 0.0016; for second dose: 156.1 vs. 129.8, <i>p</i> = 0.012), CL (88.74 vs. 124.23 mL/min, <i>p</i> = 0.0089), C_max (4232.6 vs. 3675.5 ng/mL, <i>p</i> = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, <i>p</i> = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the <i>GSTA1</i>*<i>B</i> variant. The <i>GSTA1</i> polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients.

Item Description

10.3390/pharmaceutics14020401
1999-4923