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

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.

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

“…The plasma half-life (t 1/2 ) of IP6 is short (8 min) after intravenous (i.v.) bolus administration in rats 45,65 , and values of 27 and 54 min after a 4-h i.v. infusion have been reported in hemodialyzed patients and healthy volunteers, respectively 43 .…”

“…Completed phase II studies in hemodialysis patients with calciphylaxis or coronary artery calcifications, respectively, showed good safety, tolerability, as well as encouraging efficacy [42][43][44] . IP6 is injected intravenously through the dialysis machine during hemodialysis sessions to allow it to reach therapeutic exposure despite its modest potency and short plasma half-life 45 . Both factors complicate its development as a chronic ambulatory therapy 46 .…”

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

“…Both Current treatments induce no adequate reduction of CV calcification in CKD, rendering the identification and development of promising therapeutic targets essential. Experimental rodent CKD models proffer novel promising treatments; for example, the hexasodium salt of myo-inositol hexaphosphate SNF472 has been suggested as a potent ectopic calcification inhibitor both in vitro and in vivo [20,21]. Recent studies suggest the peroxisome proliferator-activated receptor-gamma (PPARγ) and the mineralocorticoid receptor (MR) as novel molecular targets for CV complications in CKD.…”

“…A novel therapeutic option is the hexasodium salt of myo-inositol hexaphosphate SNF472, a potent calcification inhibitor in vitro [20]. SNF472 binds to the growth sites of hydroxyapatite crystals, the main constituent part of calcification deposits, thereby reducing the progression of ectopic calcification [20]. SNF472 inhibited CV calcification in adenine-induced CKD rats by up to 90% (Table 2) [20].…”

“…SNF472 binds to the growth sites of hydroxyapatite crystals, the main constituent part of calcification deposits, thereby reducing the progression of ectopic calcification [20]. SNF472 inhibited CV calcification in adenine-induced CKD rats by up to 90% (Table 2) [20]. In ex vivo analysis using plasma from HD patients, hydroxyapatite crystallization potential was reduced by SNF472 [101,102].…”