Influence of single-nucleotide polymorphisms on deferasirox Ctrough levels and effectiveness

Deferasirox (DFX) is the only once-daily oral chelator for iron overload and its pharmacokinetic has been related with response to therapy. Our aim was to evaluate DFX plasma concentrations according to single-nucleotide polymorphisms in genes involved in its metabolism (UGT1A1, UGT1A3, CYP1A1, CYP1A2 and CYP2D6) and elimination (MRP2 and BCRP1). Further aim was to define a plasma concentration cutoff value predicting an adequate response to therapy. Plasma concentrations were determined at the end of dosing interval (C-trough) using an high-performance liquid chromatography-ultraviolet method. Allelic discrimination was performed by real-time PCR. C-trough levels were influenced by UGT1A1C > T rs887829, CYP1A1C > A rs2606345, CYP1A2A > C rs762551, CYP1A2C > T rs2470890 and MRP2G > A rs2273697 polymorphisms. A DFX plasma efficacy cutoff value of 20 000 ng ml(-1) was identified; CYP1A1C > A rs2606345 AA and CYP1A2C > T rs2470890 TT genotypes may predict this value, suggesting a negative predictive role in therapy efficacy. Our data suggest the feasibility of a pharmacogenetic-based DFX dose personalization.