Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation

L'Aurelle Johnson, Paul J. Orchard, K. Scott Baker, Richard Brundage, Qing Cao, Xinjing Wang, Erica Langer, Sharein Farag-El Maasah, Julie A. Ross, Rory Remmel, Pamala A. Jacobson

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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.

Original languageEnglish (US)
Pages (from-to)1052-1062
Number of pages11
JournalJournal of Clinical Pharmacology
Volume48
Issue number9
DOIs
StatePublished - Sep 1 2008

Fingerprint

Busulfan
Cell Transplantation
Glutathione Transferase
Pharmacokinetics
Genotype
Weights and Measures
Fetal Blood
Population
Area Under Curve
Blood Cells
Bone Marrow
Prospective Studies
Pediatrics
Transplants

Keywords

  • Busulfan
  • Glutathione S-transferase
  • Pharmacokinetics
  • Polymorphisms

Cite this

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title = "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.",
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AU - Johnson, L'Aurelle

AU - Orchard, Paul J.

AU - Baker, K. Scott

AU - Brundage, Richard

AU - Cao, Qing

AU - Wang, Xinjing

AU - Langer, Erica

AU - Farag-El Maasah, Sharein

AU - Ross, Julie A.

AU - Remmel, Rory

AU - Jacobson, Pamala A.

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N2 - 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.

AB - 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.

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