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

From the Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis (Dr Johnson, Dr Brundage, Ms Farag-El Maasah, Dr Remmel, Dr Jacobson); Department of Pediatrics, Division of Hematology and Oncology, Blood and Marrow Transplantation, University of Minnesota, Minneapolis (Dr Orchard, Dr Baker); Division of Biostatistics, University of Minnesota, Minneapolis (Ms Cao); Department of Laboratory Pathology and Medicine, University of Minnesota, Minneapolis (Dr Wang); and Department of Pediatrics, Division of Pediatric Epidemiology and Clinical Research, University of Minnesota, Minneapolis (Ms Langer, Dr Ross).

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.

Key Words: Glutathione S-transferase • polymorphisms • busulfan • pharmacokinetics

Address for reprints: Pamala Jacobson, PharmD, Department of Experimental and Clinical Pharmacology, Weaver Densford Hall 7-151, 308 Harvard St SE, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; e-mail: jacob117{at}umn.edu.

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