Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation.
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 <or= .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.
Johnson
L'Aurelle
L
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Orchard
Paul J
PJ
Baker
K Scott
KS
Brundage
Richard
R
Cao
Qing
Q
Wang
Xinjing
X
Langer
Erica
E
Farag-El Maasah
Sharein
S
Ross
Julie A
JA
Remmel
Rory
R
Jacobson
Pamala A
PA
D000293:Adolescent; D000367:Age Factors; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010641:Phenotype; D012189:Retrospective Studies; D055815:Young Adult
D002066:Busulfan; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D019653:Myeloablative Agonists; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human