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?

Abstract Objectives To 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). Methods We 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)D 2 , ex vivo thromboxane B 2 (TXB 2 ) levels and plasma pharmacokinetics. Results ST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T max 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 TXB 2 generation was suppressed at 15 min and complete suppression of TXB 2 was sustained at 24 h ( p 2 exposure eightfold ( p  = 0.012) compared to niacin over the first 24 h. Conclusions This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB 2 and PGD 2 increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.