In vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D2: Is this a new immediate-release therapeutic option for niacin?

ObjectivesTo evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs).MethodsWe compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D2, ex vivo thromboxane B2 (TXB2) levels and plasma pharmacokinetics.ResultsST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with Tmax values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB2 generation was suppressed at 15 min and complete suppression of TXB2 was sustained at 24 h (p < 0.01 vs niacin). ST0702 suppressed PGD2 exposure eightfold (p = 0.012) compared to niacin over the first 24 h.ConclusionsThis two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB2 and PGD2 increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.

► We compared the niacin and niacin-aspirin prodrug ST0702 in the cynomolgus monkey. ► ST0702 was more efficacious on lipid parameters than niacin. ► ST0702 reduced COX-products associated with platelet activation and flushing. ► ST0702 attenuated post-prandial glyceamia, unlike niacin. ► ST0702 may be a new immediate-release therapeutic option for niacin.