Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification

Miguel D Ferrer; Markus Ketteler; Fernando Tur; Eva Tur; Bernat Isern; Carolina Salcedo; Pieter H Joubert; Geert J Behets; Ellen Neven; Patrick C D'Haese; Joan Perelló

doi:10.1371/journal.pone.0197061

Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification

PLoS One. 2018 May 9;13(5):e0197061. doi: 10.1371/journal.pone.0197061. eCollection 2018.

Authors

Miguel D Ferrer^{1

2}, Markus Ketteler³, Fernando Tur^{1

4}, Eva Tur¹, Bernat Isern¹, Carolina Salcedo¹, Pieter H Joubert^{1

5}, Geert J Behets⁶, Ellen Neven⁶, Patrick C D'Haese⁶, Joan Perelló^{1

4}

Affiliations

¹ Laboratoris Sanifit SL, Research and Development Department, Palma, Spain.
² Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma, Spain.
³ Division of Nephrology, Klinikum Coburg GmbH, Coburg, Germany.
⁴ University Institute of Health Sciences Research, University of the Balearic Islands, Palma, Spain.
⁵ Institute of Pharmaceutical Science, King's College, London, United Kingdom.
⁶ Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

Abstract

End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcinosis / drug therapy*
Calcinosis / etiology
Calcinosis / pathology
Cardiovascular Diseases / drug therapy*
Cardiovascular Diseases / etiology
Cardiovascular Diseases / pathology
Cholecalciferol / metabolism
Disease Models, Animal
Disease Progression
Humans
Inositol / administration & dosage*
Inositol / pharmacokinetics
Kidney Failure, Chronic / complications
Kidney Failure, Chronic / drug therapy
Kidney Failure, Chronic / pathology
Rats
Renal Insufficiency, Chronic / complications
Renal Insufficiency, Chronic / drug therapy*
Renal Insufficiency, Chronic / pathology
Uremia / complications
Uremia / drug therapy
Uremia / pathology

Substances

Cholecalciferol
Inositol

Grants and funding

This study was supported by a grant from “Fundación Genoma España/Centro para el Desarrollo Tecnológico Industrial” (CDTI) through the INNOCASH program (IC10- 129) and from private funds of Laboratoris Sanifit. MF (PTQ-11-04860), ET (PTQ-09- 01-00301) and CS (PTQ-11-04872) were co-funded by the INNCORPORA-Torres Quevedo subprogram of the “Ministerio de Economía y Competitividad”, Government of Spain. The funders (Fundación Genoma España/CDTI, Ministerio de Economía y Competitividad, the investors of Laboratoris Sanifit) provided support in the form of salaries for authors [MF, FT, ET, BI, CS, PJ, JP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.