Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients.
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.
Zwaveling
Juliette
J
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. j.zwaveling@lumc.nl
Press
Rogier R
RR
Bredius
Robbert G M
RG
van Derstraaten
Tahar R J H M
TR
den Hartigh
Jan
J
Bartelink
Imke H
IH
Boelens
Jaap Jan
JJ
Guchelaar
Henk-Jan
HJ
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
D018906:Antineoplastic Agents, Alkylating; D004247:DNA; D005982:Glutathione Transferase; D002066:Busulfan