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Pharmacogenetic study of deferasirox, an iron chelating agent

Ji Won Lee1, Hyoung Jin Kang, Ji-Yeob Choi

  • 1Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Plos One
|June 6, 2013
PubMed

Insights

Genetic variations in drug-metabolizing enzymes like UGT1A, MRP2, and BCRP are linked to deferasirox toxicities in patients with transfusion-associated iron overload. Identifying these genetic markers can help predict and manage adverse drug reactions, optimizing treatment for iron overload.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism and Transport
  • Hematology

Background:

  • Transfusion-associated iron overload is a common complication requiring chelation therapy.
  • Deferasirox is an oral iron chelator with demonstrated efficacy but potential for drug-related toxicities.
  • Individual variability in deferasirox response and toxicity necessitates investigation into underlying genetic factors.

Purpose of the Study:

  • To investigate the association between genetic polymorphisms in UDP-glucuronosyltransferase 1A (UGT1A), multi-drug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) with deferasirox-related toxicities.
  • To identify potential pharmacogenetic biomarkers for predicting deferasirox toxicity in patients with transfusion-induced iron overload.
  • To explore genetic factors influencing hepatotoxicity and creatinine elevation associated with deferasirox treatment.

Main Methods:

  • Retrospective analysis of 98 patients receiving deferasirox for transfusion-induced iron overload.
  • Genotyping of 20 functional genetic polymorphisms in UGT1A, MRP2, and BCRP.
  • Review of medical records to identify and assess drug-related toxicities, specifically hepatotoxicity and creatinine elevation.

Main Results:

  • Fifteen percent of patients developed hepatotoxicity. Patients with specific MRP2 haplotypes (carrying -1774 del and/or -24T) showed a significantly increased risk (OR=7.17, P=0.005).
  • Nine percent of patients experienced creatinine elevation. Risk factors included body weight ≥40 kg (OR=8.48, P=0.010) and homozygosity for UGT1A1*6 (OR=14.17, P=0.028).
  • Functional genetic variants in key drug-metabolizing and transport enzymes are associated with deferasirox-induced toxicities.

Conclusions:

  • Genetic variations in UGT1A, MRP2, and BCRP play a role in deferasirox-related toxicities, including hepatotoxicity and creatinine elevation.
  • Specific MRP2 haplotypes and UGT1A1*6 homozygosity may serve as predictive biomarkers for deferasirox toxicity.
  • Further research is warranted to validate these findings and establish pharmacogenetic testing for personalized deferasirox therapy.

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