Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation

Abstract

Background: Busulfan is used in preparative regimens prior to stem cell transplantation in pediatric patients. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. To date, only polymorphisms in genes encoding for glutathione-S-transferases were studied, but could only explain a small portion of the variability in PK. Aim: To investigate the effect of seven genetic markers on busulfan clearance and the effect of ontogenesis on these genetic variants in a pediatric population. Materials & methods: In an earlier study of our group seven genetic markers in GSTA1, CYP2C19, CYP39A1, ABCB4, SLC22A4 and SLC7A8 were associated with busulfan clearance in adult patients. Eighty four pediatric patients were genotyped for these markers and genotype was associated with busulfan clearance. Results & conclusion:GSTA1 and CYP39A1 were found to be associated with busulfan clearance. When combined, the two haplotypes explained 17% of the variability in busulfan clearance. Furthermore, the effect of GSTA1 haplotype on clearance was dependent on age. Original submitted 12 June 2013; Revision submitted 14 August 2013.