title: Pharmacokinetic and pharmacogenetic analysis of oral busulfan in stem cell transplantation: prediction of poor drug metabolism to prevent drug toxicity.
abstract: High dose busulfan (BU) has become a mainstay in conditioning regimens for hematopoietic stem cell transplantation (HSCT), despite its unpredictable response, narrow therapeutic index and severe toxicity. The present study provides an integration of pharmacokinetic and genetic data of 63 adults with acute myeloid leukemia (AML) preconditioned for HSCT with high dose oral BU, with the aim of defining biomarkers predictive of poor BU metabolism. BU area under the concentration time curve (AUC) demonstrated that 76% of the patients achieved target AUC; 24% required dose modification. The main findings of this study were: (1) AML patients carrying the GSTP1 rs1695 variant allele were at risk of developing supra-therapeutic BU-AUC due to reduced BU clearance. (2) Combined polymorphisms in GSTM1 and ABCB1 were associated with BU clearance and AUC rates. In conclusion, GST and ABCB1 genotyping may assist care-givers in personalizing BU dosage with less trial-and-error and may enable preemptive identification of patients at risk for BU toxicity.
authors.affiliation: Rappaport - Rambam Center for Translational Genetics, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Norberto
authors.initials: N
authors.lastname: Krivoy
authors.forename: Tsila
authors.initials: T
authors.lastname: Zuckerman
authors.forename: Hela
authors.initials: H
authors.lastname: Elkin
authors.forename: Lia
authors.initials: L
authors.lastname: Froymovich
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Edna
authors.initials: E
authors.lastname: Efrati
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002066:Busulfan / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D019172:Transplantation Conditioning
chemical_list: D002066:Busulfan; D005982:Glutathione Transferase