Pharmacokinetic and Pharmacogenetic Analysis of Oral Busulfan in Stem Cell Transplantation: Prediction of Poor Drug Metabolism to Prevent Drug Toxicity

Author(s): Norberto Krivoy, Tsila Zuckerman, Hela Elkin, Lia Froymovich, Jacob M. Rowe, Edna Efrati.

Journal Name: Current Drug Safety

Volume 7 , Issue 3 , 2012

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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.

Keywords: Busulfan, HSCT, pharmacokinetics, pharmacogenetics, SNP, toxicity, GST, ABCB1

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Article Details

Year: 2012
Page: [211 - 217]
Pages: 7
DOI: 10.2174/157488612803251324
Price: $58

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