Kidney Week

Abstract: TH-PO367

SNF472 Is More Efficacious In Vivo Than Its 4,6-bisPEGylated Derivative in Inhibiting Vascular Calcification in Rats

Session Information

• Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Ferrer, Miquel D., Sanifit Therapeutics, Palma, Spain

Miquel D. Ferrer,

• Perez, Maria del mar, Sanifit Therapeutics, Palma, Spain

Maria del mar Perez,

• Bassissi, Firas, Sanifit Therapeutics, Palma, Spain

Firas Bassissi,

• Perelló, Joan, Sanifit Therapeutics, Palma, Spain

Joan Perelló,

• Salcedo, Carolina, Sanifit Therapeutics, Palma, Spain

Carolina Salcedo,

Background

Vascular calcification (VC) is a major contributor to increased morbidity and mortality in Chronic Kidney Disease patients undergoing dialysis. Although VC is a multifactorial process, the final common pathway is deposition of solid hydroxyapatite (HAP) within the arteries. SNF472, salt of InsP6, is a selective calcification inhibitor that interferes in the formation and growth of ectopic HAP. SNF472 is currently being developed for the treatment of calciphylaxis in patients on dialysis. Inositol-1,2,3,5-tetraphosphate-4,6-bisPEG₁₀₀ (InsP4bisPEG) is an inositol phosphate derivative resulting from the PEGylation of inositol tetraphosphate (InsP4) with polyethylene glycol (PEG) 100. The aim of this study was to compare the relative bioavailability and in vivo efficacy in the inhibition of calcification of subcutaneous (s.c.) InsP4bisPEG and SNF472 at equimolar doses in rats.

Methods

S.c. pharmacokinetics (PK) of InsP4bisPEG and SNF472 were assessed in male Sprague Dawley rats after a single administration. Plasma samples were obtained and analyzed. The in vivo efficacy was evaluated in 24 male Sprague Dawley rats, divided into three groups of eight rats receiving placebo (NaCl 0.9%) or equimolar doses (36 µmol/kg) of SNF472 or InsP4bisPEG. Vascular calcification was induced by 3 consecutives daily s.c. administrations of 150 kIU/kg vitamin D3, starting on day 1. Rats were sacrificed 5 days after induction of calcification, and aorta was collected for calcium analysis.

Results

The plasma C_max of InsP4bisPEG was 9.8 µM, at a t_max of approximately 30 minutes. AUC_0-t was 13.1 μmol/h/L and the terminal half-life (t_1/2) was 46 min. SNF472 showed a plasma C_max of 7.4 µM at around 15 min, with an AUC_0-t of 2.5 μmol/h/L and a terminal t_1/2 of 17 min. SNF472 treated animals presented significantly lower calcium levels in aorta, which were 38% and 55% lower than placebo and InsP4bisPEG treated animals, respectively.

Conclusion

InsP4bisPEG is more bioavailable than SNF472 and presents a longer plasma half-life. However, SNF472 is more efficacious inhibiting aorta calcification than this InsP6 PEGylated derivative in an in vivo vitamin D3 rat model at 36 mmol/kg. This is probably due to the larger affinity of SNF472 for HAP crystals.

Funding

• Commercial Support –