Preclinical Pharmacokinetics, Pharmacodynamics and Safety of Sucroferric Oxyhydroxide

Abstract

Sucroferric oxyhydroxide (VELPHORO®) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of 59Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity.

Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: A randomized, open‐label, multicentre, 12‐week phase III study

“…Regarding the clinical laboratory tests, increasing trends in serum ferritin, TSAT, and haemoglobin levels were observed in the PA21 group as well as the previous Phase III study . However, the previous non‐clinical and clinical studies of PA21 confirmed that the iron absorption level was consistently low and no iron accumulation was indicated in the previous long‐term study . When comparing the current study and the previous Phase III study, the absolute ferritin values and fluctuation range of ferritin were higher in the previous study.…”

Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis

“…Lanthanum binds phosphate through its trivalent cation [ 13 ]. Recently, iron (e.g., ferric citrate and sucroferric oxyhydroxide) has also proved effective in lowering phosphate by impeding the absorption of phosphate in the stomach without evidence of toxicity [ 14 , 15 ]. The crucial question, however, is the relative impact of these agents on patient-important outcomes, particularly on mortality.…”

Phosphate binders for the treatment of chronic kidney disease: role of iron oxyhydroxide

“…51 With regard to excretion of the drug in preclinical studies, radioactivity was detected only in feces and not in bile or urine. 49 A further important point is that CKD patients often have to take many medications throughout the day and this could expose them to the risk of drug interactions.…”