SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels

Abstract

Background: Cardiovascular calcification (CVC) is a major concern in hemodialysis (HD) and the loss of endogenous modulators of calcification seems involved in the process. Phytate is an endogenous crystallization inhibitor and its low molecular mass and high water solubility make it potentially dialyzable. SNF472 (the hexasodium salt of phytate) is being developed for the treatment of calciphylaxis and CVC in HD patients. We aimed to verify if phytate is lost during dialysis, and evaluate SNF472's behaviour during dialysis.

Methods: Dialyzability was assessed in vitro using online-hemodiafiltration and high-flux HD systems in blood and saline. SNF472 was infused for 20 min and quantified at different time points.

Results: Phytate completely dialyzed in 1 h at low concentrations (10 mg/l) but not when added at 30 or 66.67 mg/l SNF472. In bypass conditions, calcium was slightly chelated during SNF472 infusion but when the system was switched to dialysis mode the calcium in the bath compensated this chelation.

Conclusion: Phytate dialyses with a low clearance. The administration of SNF472 as an exogenous source of phytate allows to attain supra-physiological levels required for its potential therapeutic properties. As SNF472 is infused during the whole dialysis session, the low clearance would not affect the drug's systemic exposure.

Keywords: Cardiovascular calcification; End-stage renal disease; Hemodialysis; Phytate.

Fig. 1

Scheme of the infusion system

Fig. 2

In vitro dialysability and stability of SNF472 under different experimental conditions. (A) 66.67 mg/l SNF472, pre-filter sampling; (B) 66.67 mg/l SNF472, post-filter sampling; (C) 30 mg/l SNF472, pre-filter sampling; (D) 30 mg/l SNF472, post-filter sampling; (E) 10 mg/l SNF472, pre-filter sampling; (F) 10 mg/l SNF472, post-filter sampling; (G) 30 mg/l SNF472 in saline with OL-HDF; (H) in vitro stability of 2.5 and 15 mg/l SNF472 in human blood at 37 °C. (A-F) SNF472 was infused at different concentrations for 20 min in 1 l blood. OL-HDF experiments performed in triplicate, mean ± SEM is represented HD and bypass experiments performed in single experiments. OL-HDF: online-hemodiafiltration; HD: hemodialysis; PMMA: polymethylmethacrylate membrane

Fig. 3

Creatinine clearance and SNF472 effect on calcium levels in in vitro dialysis systems. SNF472 was infused at different concentrations for 20 min in 1 l blood. (A, B) 66.67 mg/l SNF472; (C, D) 30 mg/l SNF472; (E, F) 10 mg/l SNF472. In (B, D and F) solid lines represent total calcium while dashed lines represent ionized calcium. OL-HDF experiments performed in triplicate, mean ± SEM is represented. HD and bypass experiments performed in single experiments. OL-HDF: online-hemodiafiltration; HD: hemodialysis; PMMA: polymethylmethacrylate membrane

Fig. 4

In vitro dialysability of 30 mg/l SNF472 under different experimental conditions in saline samples. SNF472 was infused at 30 mg/l for 20 min in 1 l saline. (A) Pre-filter sampling; (B) Post-filter sampling; (C) Creatinine clearance; (D) Total (solid lines) and ionized (dashed lines) calcium levels. OL-HDF: online-hemodiafiltration

Fig. 5

In vitro SNF472 dialysability in blood and saline in the absence of calcium in the dialysis bath. SNF472 was infused for 20 min at (A) 66.67 mg/l in 1 l blood or (B) 30 mg/l in 1 l saline; (C) Creatinine clearance; (D) Total (solid lines) and ionized (dashed lines) calcium levels