Iron sucrose and ferric carboxymaltose: no correlation between physicochemical stability and biological activity

Significance Statement

Intravenous iron preparations are widely used for the treatment of renal anemia. In an earlier in vitro study with iron sucrose in liver parenchyma HepG2-cells we predicted a possible iron accumulation in the liver and a T2*-MRI study demonstrated iron deposition in the liver and other tissues in hemodialysis patients receiving iron sucrose and ferric gluconate after longtime treatment with intravenous iron. Importantly, iron overload was not detectable by laboratory blood tests. This clearly demonstrates that findings from preclinical studies can often predict the in vivo situation. With ferric carboxymaltose, which launched on the market recently, so far no reports exist about possible iron deposition. Therefore, we performed a non-clinical study with iron sucrose and ferric carboxymaltose and found that in contrast to iron sucrose, ferric carboxymaltose is not incorporated by liver parenchyma cell. These findings indicate that liver iron overload with ferric carboxymaltose is very unlikely. Chemical stability of ferric carboyxmaltose is higher compared to iron sucrose, but interestingly biostability order was reversed in human serum. In addition, ascorbic acid, which is discussed as an adjuvant therapy to improve iron availability, showed an increase in transferrin saturation with iron sucrose, but a decrease with ferric carboxymaltose, which may have implications on hepcidin expression in vivo.

Journal Reference

Praschberger M, Haider K, Cornelius C, Schitegg M, Sturm B, Goldenberg H, Scheiber-Mojdehkar B. Biometals. 2015 ;28(1):35-50.

Department of Medical Chemistry, Medical University of Vienna, Waehringerstr. 10, 1090, Vienna, Austria.

Abstract

Intravenous iron preparations, like iron sucrose (IS) and ferric carboxymaltose (FCM) differ in their physicochemical stability. Thus differences in storage and utilization can be expected and were investigated in a non-clinical study in liver parenchyma HepG2-cells and THP-1 macrophages as models for toxicological and pharmacological target cells. HepG2-cells incorporated significant amounts of IS, elevated the labile iron pool (LIP) and ferritin and stimulated iron release. HepG2-cells had lower basal cellular iron and ferritin content than THP-1 macrophages, which showed only marginal accumulation of IS and FCM. However, FCM increased the LIP up to twofold and significantly elevated ferritin within 24 h in HepG2-cells. IS and FCM were non-toxic for HepG2-cells and THP-1 macrophages were more sensitive to FCM compared to IS at all concentrations tested. In a cell-free environment redox-active iron was higher with IS than FCM. Biostability testing via assessment of direct transfer to serum transferrin did not reflect the chemical stability of the complexes (i.e., FCM > IS). Effect of vitamin C on mobilisation to transferrin was an increase with IS and interestingly a decrease with FCM. In conclusion, FCM has low bioavailability for liver parenchyma cells, therefore liver iron deposition is unlikely. Ascorbic acid reduces transferrin-chelatable iron from ferric carboxymaltose, thus effects on hepcidin expression should be investigated in clinical studies.

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About the Authors

This study was performed by Prof. Barbara Scheiber-Mojdehkar`s team at the Department of Medical Chemistry at the Medical University in Vienna. Scheiber-Mojdehkar`s work focuses on several aspects of iron metabolism, especially on treatment of iron deficiency in haemodialysis patients. Most patients require administration of intravenous iron preparations to treat renal anaemia. Although available intravenous iron preparations are clinically effective, significant morbidity from both dose–dependent and –independent side effects have been reported. In her research, she focuses on influence of intravenous iron compounds (in use or under development) on cellular iron metabolism and biostability of iron preparations in non-clinical studies.

Contact : Barbara Scheiber-Mojdehkar, Department of Medical Chemisty , Medical University of Vienna, Waehringerstr. 10, A-1090 Vienna, Austria

Email: [email protected]