Ferric citrate Other names: Iron(III) citrate

Ferric citrate coordination complex is specifically designed to have a high surface area and a defined molar ratio of ferric iron to citrate. The high surface area of ferric citrate coordination complex impacts ferric iron solubility at physiological pH and allows part of ferric iron to be absorbed and supply iron to the metabolic pathway.

Ferric citrate coordination complex has a dual mechanism of action, one that is associated with providing a source of ferric iron and one associated with decreasing the absorption of phosphorous. The dual mechanism of action result in a direct impact on reducing functionally active intact fibroblast growth factor 23 (iFGF-23).

Following oral administration, soluble ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the gastrointestinal (GI) tract. After transport through the enterocytes into the blood, oxidized ferric iron circulates bound to the plasma protein transferrin, and can be incorporated into haemoglobin.

The non-absorbed part of the complex reacts with dietary phosphate in the GI tract and precipitates phosphate as ferric citrate phosphate complex. This compound is insoluble and is excreted in the stool, reducing the amount of phosphate that is absorbed from the GI tract. By binding phosphate in the GI tract and decreasing absorption, ferric citrate coordination complex lowers the levels of serum phosphorus. Following absorption, citrate is converted into bicarbonate by the tissues.

Formal pharmacokinetic studies have not been performed.

Following oral administration, soluble ferric iron is reduced from the ferric to the ferrous form by ferric reductase in the gastrointestinal (GI) tract. After transport through the enterocytes into the blood, oxidised ferric iron circulates bound to the plasma protein transferrin. It is distributed mainly to the liver, spleen, bone narrow and utilised by incorporation into red blood cells.

Unabsorbed iron from ferric citrate coordination complex interacts with phosphate in the GI tract to form a ferric citrate phosphate complex, an insoluble complex excreted in stool.

Following absorption, citrate is converted into bicarbonate by the tissues.

The target organ for primary toxicity of ferric citrate coordination complex in repeat-dose oral toxicity studies in rats and dogs is the gastrointestinal tract. Brown pigmentation reflecting iron overload and leading to liver injury was observed in ferric citrate-treated dogs, the most sensitive species, in a 42-week study. The safety margin at the no-observed-adverse-effect level (NOAEL) for the proposed maximal human therapeutic dose of 200 mg/kg (12 g/day) corresponds to 1.1 based on a body surface area.

Ferric citrate coordination complex was neither mutagenic in the bacterial reverse mutation assay (Ames test) nor clastogenic in the chromosomal aberration test in Chinese hamster fibroblasts.

Data from carcinogenicity studies have shown that iron compounds and citric acid are not carcinogenic in mice and rats when administered intramuscularly or subcutaneously.

The potential for ferric citrate coordination complex to impair reproductive performance or to cause foetal malformation has not been evaluated.