title: Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients.
abstract: High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. j.zwaveling@lumc.nl
authors.forename: Juliette
authors.initials: J
authors.lastname: Zwaveling
authors.forename: Rogier R
authors.initials: RR
authors.lastname: Press
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Tahar R J H M
authors.initials: TR
authors.lastname: van Derstraaten
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006504:Hepatic Veno-Occlusive Disease / Q000150:complications / Q000175:diagnosis; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D015233:Models, Statistical; D011110:Polymorphism, Genetic / Q000235:genetics; D011153:Population; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004247:DNA; D005982:Glutathione Transferase; D002066:Busulfan