Sucroferric oxyhydroxide

Sucroferric oxyhydroxide contains a mixture of polynuclear iron(III)-oxyhydroxide (pn-FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract.

Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption.

Sucroferric oxyhydroxide works by binding phosphate in the gastrointestinal tract and thus the serum concentration is not relevant for its efficacy. Due to the insolubility and degradation characteristics of sucroferric oxyhydroxide, no classical pharmacokinetic studies can be carried out, e.g. determination of the distribution volume, area under the curve, mean residence time, etc.

In 2 Phase 1 studies, it was concluded that the potential for iron overload is minimal and no dose dependent effects were observed in healthy volunteers.

Absorption

The active moiety of sucroferric oxyhydroxide, pn-FeOOH, is practically insoluble and therefore not absorbed. Its degradation product, mononuclear iron species, can however be released from the surface of pnFeOOH and be absorbed.

The absolute absorption studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that systemic absorption was very low (≤1% of the administered dose).

The iron uptake from radiolabelled sucroferric oxyhydroxide drug substance, 2,000 mg iron in 1 day was investigated in 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron in the blood was estimated to be 0.43% (range 0.16–1.25%) on Day 21, in pre-dialysis patients 0.06% (range 0.008–0.44%) and in haemodialysis patients 0.02% (range 0–0.04%). Blood levels of radiolabelled iron were very low and confined to the erythrocytes.

Distribution

The distribution studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that pn-FeOOH is distributed from the plasma to the liver, spleen and bone marrow, and utilized by incorporation into red blood cells.

In patients, absorbed iron is expected to be also distributed to the target organs, i.e. liver, spleen and bone marrow, and utilized by incorporation into red blood cells.

Biotransformation

The active moiety of sucroferric oxyhydroxide, pn-FeOOH, is not metabolised. However, the degradation product of sucroferric oxyhydroxide, mononuclear iron species, can be released from the surface of polynuclear iron(III)-oxyhydroxide and be absorbed. Clinical studies have demonstrated that the systemic absorption of iron from sucroferric oxyhydroxide is low.

In vitro data suggest that the sucrose and starch components of the drug substance can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood.

Elimination

In animal studies with rats and dogs administered ⁵⁹Fe-sucroferric oxyhydroxide drug substance orally, radiolabelled iron was recovered in the faeces but not the urine.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Effects seen in the rabbit embryo-foetal development toxicity study (skeletal variations and incomplete ossificaton) are related to exaggerated pharmacology, and likely not relevant for patients. Other reproduction toxicity studies showed no adverse effects.

Carcinogenicity studies were performed in mice and rats. There was no clear evidence of a carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 2-years treatment, but this was considered a species-specific effect with no diverticula/cysts seen in long term studies in rats or dogs. In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid of male rats given the highest dose of sucroferric oxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect of the drug, and not clinically relevant.