ICL670 Removes Cardiac Iron in a Gerbil Model of Iron Overload.

Abstract

Introduction: Deferasirox (ICL670) is a novel tridentate oral iron chelator currently being evaluated for the treatment of transfusional iron overload. Phase III clinical trials have demonstrated that once-daily ICL670 (20 mg/kg) is equally effective at controlling liver iron concentration as standard deferoxamine therapy (40 mg/kg/day, 5 days per week). While ICL670's long serum half-life should offer good protection against cardiac iron accumulation, little is known regarding its ability to remove stored cardiac iron. Therefore, we compared the relative efficacy of ICL670, deferiprone (L1), and deferoxamine (DFO) in removing cardiac iron from iron-loaded gerbils.Methods: 37 8–10 week old female gerbils underwent ten weekly iron dextran injections of 200 mg/kg/D, followed by a 13 day equilibration period. Five animals were then sacrificed to determine pre-chelation iron burdens. Chelation was initiated in 3 groups of 8 animals (ICL670 100 mg/kg/D po QD, L1 375 mg/kg/D po divided TID, DFO 200 mg/kg/D sub Q divided BID) five days per week and maintained for 12 weeks. The remaining 8 animals received sham chelation. All animals underwent ECG and treadmill assessment at baseline, following iron loading, and after completing chelation therapy. Animals were sacrificed for liver and heart iron measurement (Mayo Medical Laboratory) and semiquantitative histology. Hearts were evaluated for iron loading/distribution, tissue fibrosis, and myocyte hypertrophy, while livers were scored for iron loading/distribution and fibrosis.Results: Chelator-independent iron excretion and redistribution was evident, unlike in humans. Cardiac and liver iron contents fell 30.4% and 23.2%, respectively, with sham chelation; all subsequent chelator comparisons are reported with respect to the sham-chelated animals. ICL670 reduced cardiac iron content 20.5%. There were no changes in cardiac weight, myocyte hypertrophy, fibrosis, or wet-to-dry weight ratio.ICL670 treatment reduced liver iron content 51%. Iron elimination was greatest in hepatocytes with no detectable Kupfer-cell iron clearance.L1 produced comparable reductions in cardiac iron content (18.6%). Wet weight cardiac iron concentration fell nearly 30% but this was offset by greater cardiac mass (16.5% increase). Histologic analysis demonstrated decreased iron staining but increased myocyte hypertrophy. L1 decreased liver iron content 24.9%. Wet weight liver iron concentration fell 43.8% but was offset by a 30% increase in liver weight and water content. Iron elimination was balanced between Kupfer cells and hepatocytes. DFO did not reduce biochemically-assayed cardiac or liver iron content, although it improved histologic iron scores in both organs. Hearts from DFO treated animals were enlarged and had greater fibrosis.Cardiac and liver iron contents were closely correlated (r = 0.66), but ICL670 animals had lower hepatic iron contents for any given cardiac iron content. Iron loading broadened QRS duration by 10.6%; this effect was antagonized by both L1 and ICL670 therapy. PR, QRS, and QTc interval were weakly correlated with cardiac and liver iron contents. Treadmill exercise time was independent of chelation therapy.Conclusion: ICL670 and L1 were equally effective in removing stored cardiac iron in a gerbil animal model but ICL670 removed more hepatic iron for a given cardiac iron burden.