Iron uptake and ferrokinetics in healthy male subjects of an iron-based oral phosphate binder (SBR759) labeled with the stable isotope (58)Fe.

Hans-Peter Gschwind,Friedhelm Von Blanckenburg,Kirsten Van Zuilen,Dietmar G Schmid,Daniel Kaufmann,Alan J Slade,Marcus Oelze,Sylvie Stitah,Piet Swart

doi:10.1039/c4mt00126e

Abstract

SBR759 is a novel polynuclear iron(III) oxide-hydroxide starch·sucrose·carbonate complex being developed for oral use in chronic kidney disease (CKD) patients with hyperphosphatemia on hemodialysis. SBR759 binds inorganic phosphate released by food uptake and digestion in the gastro-intestinal tract increasing the fecal excretion of phosphate with concomitant reduction of serum phosphate concentrations. Considering the high content of ∼20% w/w covalently bound iron in SBR759 and expected chronic administration to patients, absorption of small amounts of iron released from the drug substance could result in potential iron overload and toxicity. In a mechanistic iron uptake study, 12 healthy male subjects (receiving comparable low phosphorus-containing meal typical for CKD patients: ≤1000 mg phosphate per day) were treated with 12 g (divided in 3 × 4 g) of stable (58)Fe isotope-labeled SBR759. The ferrokinetics of [(58)Fe]SBR759-related total iron was followed in blood (over 3 weeks) and in plasma (over 26 hours) by analyzing with high precision the isotope ratios of the natural iron isotopes (58)Fe, (57)Fe, (56)Fe and (54)Fe by multi-collector inductively coupled mass spectrometry (MC-ICP-MS). Three weeks following dosing, the subjects cumulatively absorbed on average 7.8 ± 3.2 mg (3.8-13.9 mg) iron corresponding to 0.30 ± 0.12% (0.15-0.54%) SBR759-related iron which amounts to approx. 5-fold the basal daily iron absorption of 1-2 mg in humans. SBR759 was well-tolerated and there was no serious adverse event and no clinically significant changes in the iron indices hemoglobin, hematocrit, ferritin concentration and transferrin saturation.

Highlights

This study provided insight into the applicability of the MC-ICP-MS technique in measuring isotope-labeled iron in human blood and plasma
There was no sign of overt or acute iron toxicity as there were no clinically significant changes in laboratory parameters hemoglobin, hematocrit, ferritin and transferrin saturation (TSAT) (Table 3)
The mean TSAT values at Days-1, 11 and 21 were 35.8, 24.3 and 24.0% which were in the normal range (16–45%) and distinctly below the toxic limit of 85% leading to labile redox active plasma iron (LPI)

Summary

Introduction

SBR759 is a novel polynuclear iron(III) oxide–hydroxide starchÁsucroseÁcarbonate complex being developed for oral use in chronic kidney disease (CKD) patients with hyperphosphatemia on hemodialysis. Lanthanum carbonate demonstrates significant phosphate-binding properties and good efficacy but has been associated with hypercalcemia (Hutchison, 2009) (Hutchison, 2005) (D’Haese, 2003).. Lanthanum carbonate demonstrates significant phosphate-binding properties and good efficacy but has been associated with hypercalcemia (Hutchison, 2009) (Hutchison, 2005) (D’Haese, 2003).2 Studies in both rats (Slatopolsky, 2005) and humans (Spasovski, 2006) have suggested that long-term lanthanum administration carries the risk of blood and tissue accumulation. SBR759 is a novel polynuclear iron(III) oxide–hydroxideÁstarch– sucroseÁcarbonate complex designed for oral use to bind with high affinity and excrete inorganic phosphate. In phase II dose titration studies assessing Asian patients requiring hemodialysis, SBR759 demonstrated superior efficacy in phosphate control compared with sevelamer-HCl, an approved phosphate binder (Chen, 2011) (Fukagawa, 2014). SBR759 has been shown to be an effective phosphate binder in vivo and shows rapid, selective, and high in vitro binding of phosphate at both highly acidic and neutral pH with phosphate-binding capacity similar to currently available agents (Hergesell, 1999)8a (Hergesell, 1999).8b SBR759 lowered serum phosphate concentrations rapidly and to a clinically meaningful extent across a wide dose range with good tolerability (Block, 2010). In phase II dose titration studies assessing Asian patients requiring hemodialysis, SBR759 demonstrated superior efficacy in phosphate control compared with sevelamer-HCl, an approved phosphate binder (Chen, 2011) (Fukagawa, 2014).

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Results

Conclusion