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

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 28mg/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 48h (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 95min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48h 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 15min and complete suppression of TXB ₂ was sustained at 24h (p<0.01 vs niacin). ST0702 suppressed PGD ₂ exposure eightfold (p=0.012) compared to niacin over the first 24h. 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.