title: 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 (59)Fe-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.
authors: Department of Health Sciences, University of Milan, Renal Division, San Paolo Hospital, Via A. Di Rudinì, 8 20142 Milan, Italy. mario.cozzolino@unimi.it.
authors: Mario
authors: M
authors: Cozzolino
authors: Felix
authors: F
authors: Funk
authors: Viatcheslav
authors: V
authors: Rakov
authors: Olivier
authors: O
authors: Phan
authors: Isaac
authors: I
authors: Teitelbaum
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D004338:Drug Combinations; D005290:Ferric Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065569:Gastrointestinal Absorption; D006801:Humans; D054559:Hyperphosphatemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D010710:Phosphates / Q000097:blood*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D018570:Risk Assessment; D013395:Sucrose / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014511:Uremia / Q000097:blood / Q000503:physiopathology; D061205:Vascular Calcification / Q000097:blood / Q000209:etiology / Q000517:prevention & control
chemical_list: D002614:Chelating Agents; D004338:Drug Combinations; D005290:Ferric Compounds; D010710:Phosphates; C000599459:sucroferric oxyhydroxide; D013395:Sucrose