PLoS ONE (Jan 2013)

Pharmacogenetic study of deferasirox, an iron chelating agent.

  • Ji Won Lee,
  • Hyoung Jin Kang,
  • Ji-Yeob Choi,
  • Nam Hee Kim,
  • Mi Kyung Jang,
  • Chang-Woo Yeo,
  • Sang Seop Lee,
  • Hyery Kim,
  • June Dong Park,
  • Kyung Duk Park,
  • Hee Young Shin,
  • Jae-Gook Shin,
  • Hyo Seop Ahn

DOI
https://doi.org/10.1371/journal.pone.0064114
Journal volume & issue
Vol. 8, no. 5
p. e64114

Abstract

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Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing -1774 del and/or -24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79-28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7-43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34-150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.