Glutathione S-transferase Polymorphisms Are Not Associated With Population Pharmacokinetic Parameters of Busulfan in Pediatric Patients

Abstract

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

“…BU was observed in pediatric GSTA1*B patients; 21,22 and accordingly increased BU CL correlated with GSTA1*A haplotype. 17,39 However, a few studies conducted in adults and children 15,31,32 failed to show such an association, which might be due to low sample size, 15 31 or different methods of estimating BU PK might also have contributed to the conflicting observations. Our study included patients receiving only myeloablative conditioning regimen with i.v.…”

“…BU CL in individuals with combined GSTM1 and GSTT1 null genotypes, but not in individuals with GSTM1 null genotype alone, 39 whereas others reported absence of such association. 17,26,27,[30][31][32] The compensatory action of other GST isoforms to defective enzyme activity has been also demonstrated. 39 We did not find clear combined effect or interaction between GSTM1 and GSTA1 genotypes.…”

“…15,17,26,30,32 GST genetic variants and clinical outcomes of HSCT Better EFS was seen in homozygous GSTA1*A2 patients, which is likely due to a significantly lower BU levels seen in these individuals. Indeed, lower Css correlated with better EFS, which is in accordance with our observation 38 and with previous reports.…”

“…This finding is nevertheless contrary to the hypothesis that increased activity of GSTA in GSTM1 null individuals might deplete GSH causing damage to liver and occurrence of VOD. 41 None of the few studies that looked into an association between GST genotypes and clinical outcomes 17,28,32 reported correlation between GSTA1 genotypes and EFS or VOD, which may be due to the low incidence of VOD, inclusion of patients on nonmyeloablative regimen, other events, non-investigated factors that may potentiate GSTA1 effect (for example, gender), dose adjustment or low sample size. We did not observe any association of VOD with GSTM1 genotypes, in agreement with previous studies 15,17,28 and contrary to a report on higher VOD incidence in GSTM1 null carriers, which could be attributed to the different patient population.…”

“…BU in both adults and children; 17,[26][27][28][29][30] others did not find this association. 15,31,32 In a small pilot study, we have shown that polymorphisms in GSTM1 might influence the PK of BU. 15 The present work was undertaken to confirm this finding and to allow more detailed insight into GST variants in a larger cohort.…”