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?
OBJECTIVE
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 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.
School of Medicine and Medical Science, University College Dublin, Ireland.
Mark T
MT
Ledwidge
Fiona
F
Ryan
David M
DM
Kerins
Damian
D
O'Connell
Gene
G
Cefali
Shona
S
Harmon
Michael
M
Jones
John F
JF
Gilmer
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D001241:Aspirin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D008078:Cholesterol, LDL / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006943:Hyperglycemia / Q000097:blood / Q000517:prevention & control; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007547:Isosorbide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids / Q000097:blood*; D008252:Macaca fascicularis; D008954:Models, Biological; D009525:Niacin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019518:Postprandial Period; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000097:blood*; D012459:Salicylates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D001786:Blood Glucose; D008078:Cholesterol, LDL; D016861:Cyclooxygenase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D011355:Prodrugs; D012459:Salicylates; D014280:Triglycerides; C573785:isosorbide-5-nicotinate-2-aspirinate; D009525:Niacin; D013929:Thromboxane B2; D001241:Aspirin; D015230:Prostaglandin D2; D007547:Isosorbide