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

Michaud, Véronique; Tran, My Dung; Pronovost, Benoît; Bouchard, Philippe; Bilodeau, Sarah; Alain, Karine; Vadnais, Barbara; Franco, Martin; Bart, François; Turgeon, Jacques

doi:10.3390/pharmaceutics11090440

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…For example, Abbasi et al 14 stated that GSTA1 was not significant influence factor of intravenous (IV) Bu clearance. However, Michaud et al 15 reported that adult patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Yin et al 16 stated adult patients with the GSTA1 *A/*B genotype had a significantly higher AUC, higher peak concentration (C max ) and lower clearance (CL).…”

Section: Introductionmentioning

confidence: 99%

Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

Yuan¹,

Sun²,

Feng³

et al. 2021

PGPM

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Purpose The aim of this study was to develop a novel busulfan dosing regimen, based on a population pharmacokinetic (PPK) model in Chinese children, and to achieve better area under the concentration-time curve (AUC) targeting. Patients and Methods We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulated patients, and has been verified on real patients. Limited sampling strategy (LSS) was established by Bayesian forecasting. Mean absolute prediction error (MAPE) and relative root mean Squared error (rRMSE) were calculated to evaluate predictive accuracy. Results A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, body surface area (BSA) and aspartate aminotransferase (AST) were found to be significant covariates of Bu clearance, and BSA had significant impact of the volume of distribution. Moreover, two equations were obtained for recommended dose regimens: dose (mg)=34.14×BSA (m 2 )+3.75 (for GSTA1 *A/*A ), Dose (mg)=30.99×BSA (m 2 )+3.21 (for GSTA1 *A/*B ). We also presented a piecewise dosage based on BSA categories for each GSTA1 mutation. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision (rRMSE=1.026%, MAPE=6.55%). Conclusion We recommend a GSTA1 -BSA and BSA-based dosing (Q6 h) based on a PPK model for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C 2h and C 4h ) provides convenience for therapeutic drug monitoring (TDM) in the future.

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Section: Introductionmentioning

confidence: 99%

Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

Yuan¹,

Sun²,

Feng³

et al. 2021

PGPM

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“…More clarification is needed to establish a thorough understanding of the role played by CYP39A1. In adults, many authors confirmed the impacts of GSTA1 in Asians and Caucasians (Supplementary Table S1), such as Kim et al in Koreans [30], Terakura et al in Japanese [14], and Michaud et al in Canadians [40].…”

Section: Discussionmentioning

confidence: 78%

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

et al. 2022

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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 S-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 GST 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 GSTA1 was genotyped by Sanger sequencing, and GSTM1 and GSTP1 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 GSTA1*B and of GSTM1 and GSTP1* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with GSTA1*B had a statistically significant impact on the PK of busulfan, whereas those with GSTM1 and GSTP1 did not (p > 0.05). The carriers of GSTA1*B showed a significant difference compared to noncarriers in terms of t1/2 (for first dose: 161.9 vs. 134.3 min, p = 0.0016; for second dose: 156.1 vs. 129.8, p = 0.012), CL (88.74 vs. 124.23 mL/min, p = 0.0089), Cmax (4232.6 vs. 3675.5 ng/mL, p = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, p = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the GSTA1*B variant. The GSTA1 polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients.

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“…A similar pattern was observed in urine, with EXE-cys, DHE-cys, and DHE-Gluc comprising 63%, 19%, and 16% of the total EXE metabolites, respectively. (34,35) and in Hardy Weinberg equilibrium. GSTM1 genotyping results indicated that 42 subjects exhibited the GSTM1 null genotype (62%), 18 subjects had one copy of GSTM1 (26%), while only 6 subjects had both copies present (9%).…”

Section: Table 1 Rate Of Exe-gsmentioning

confidence: 99%

“…The GSTA1*B allele has been linked to lower hepatic expression of GSTA1 and altered metabolism of certain medications (32,33). In the Caucasian population, the GSTA1*B allele has a minor allele frequency (MAF) of 0.43-0.49 (34,35). Additionally, a polymorphic whole-gene deletion of GSTM1 has been identi ed (MAF of 0.48-0.57 in Caucasian populations) (36).…”

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confidence: 99%

Influence of glutathione-S-transferase polymorphisms on the metabolism of the potent aromatase inhibitor, exemestane

Teslenko

Trudeau

Luo

et al. 2022

Preprint

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Background:Exemestane (EXE) is used to treat post-menopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17β-dihydroexemestane (17β-DHE), is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the effects of genetic variation in EXE-metabolizing GST enzymes on overall EXE metabolism.Methods:Seventy-five normal human liver tissue bank specimens, and plasma and urine from 68 ER+ breast cancer patients receiving EXE, were included in this study. Samples were genotyped for GSTA1 and GSTM1 by real-time PCR. The EXE-GS and DHE-GS conjugation rates in human liver specimens and levels of EXE-cys, DHE-cys and DHE-Gluc in plasma and urine were determined by UPLC/MS.Results:Ex vivo assays examining human liver revealed the GSTA1 *B/*B genotype was associated with significant decreases in EXE-GS (26%, p=0.034) and DHE-GS (15%, p=0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the GSTA1 *B*B genotype was associated with significant decreases in both EXE-cys (29%, p=0.0056) and DHE-cys (34%, p=0.032). A near-significant (ptrend=0.060) trend was observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary DHE-Gluc levels were significantly increased (36%, p=0.00097; and 52%, p=0.0089, respectively) in patients with the GSTA1 *B*B genotype. No significant correlations were observed between GSTM1 genotype and EXE metabolite levels.Conclusions:These data suggest that the GSTA1*B allele is associated with interindividual variability in EXE metabolism and may play a role in overall response to EXE.Trial registration: retrospectively registered

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

Cited by 17 publications

References 39 publications

Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

Optimization of Busulfan Dosing Regimen in Pediatric Patients Using a Population Pharmacokinetic Model Incorporating GST Mutations

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

Influence of glutathione-S-transferase polymorphisms on the metabolism of the potent aromatase inhibitor, exemestane

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