Glutathione S‐Transferase A1 Genetic Variants Reduce Busulfan Clearance in Children Undergoing Hematopoietic Cell Transplantation

Abstract

The effect of glutathione S-transferase variants on pediatric busulfan metabolism was investigated by noncompartmental and population pharmacokinetic modeling. Twenty-nine children who underwent related or unrelated bone marrow or umbilical cord blood hematopoietic cell transplant were retrospectively studied. GSTA1, GSTP1, and GSTM1 variants were explored for their effects on busulfan exposures. Noncompartmental pharmacokinetic analyses showed that carriers of GSTA1*B had a 2.6-fold higher busulfan area under the curve and concentration at steady state compared with noncarriers (P ≤ .01). Population pharmacokinetic modeling demonstrated that carriers of GSTA1*B reduced busulfan clearance by 30%. Monte Carlo simulations were then performed to assess busulfan dosing regimens based on GSTA1 genotypes. Simulations determined that dosing based on GSTA1 genotype, weight, and age resulted in fewer children exceeding the upper therapeutic limit compared with dosing using age and weight only. Larger, prospective studies are needed to confirm these findings.

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…Given that TDM is performed in these children, an association with pharmacokinetics variability after the first BU dose does not necessarily reflect an association with disease outcome. 35 For example, three patients out of 28 (10.7%) enrolled in this study developed VOD and only one had the GSTM1-null genotype. BU exposure was slightly higher in patients with VOD compared with those without this complication; however, difference did not reach significance (P ¼ 0.08).…”

“…Two other studies that analyzed the GSTM1 gene did not find any significant correlation between first-dose pharmacokinetic variability and the GSTM1-null genotype. 33,35 The difference in the patient population and treatment schedule or other factors contributing to this variability may account for a discrepancy seen across studies. Interestingly, among the patients we analyzed, 50% had C ss values below the lower target level limit, similar to other studies.…”

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

“…Our observation is in accordance with the functional studies suggesting higher GSTA activity in GSTA1*A carriers 10,22,24 and is also supported by several previous reports. 17,[26][27][28][29][30] Decreased CL following oral BU was seen in adults and children with GSTA*B haplotype; 17,29,31 a significant decrease in CL following i.v. BU was observed in pediatric GSTA1*B patients; 21,22 and accordingly increased BU CL correlated with GSTA1*A haplotype.…”

“…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.…”

“…Although some studies have shown that GSTA1 genotypes influence the PK of oral and i.v. 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.…”