Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects.
Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.
Lai
Eseng
E
Merck Research Laboratories, Rahway, NJ 07065, USA. eseng_lai@merck.com
Schwartz
Jules I
JI
Dallob
Aimee
A
Jumes
Patricia
P
Liu
Fang
F
Kraft
Walter K
WK
Royalty
Jane
J
Chodakewitz
Jeffrey A
JA
McCrary Sisk
Christine
C
Radziszewski
Waldemar
W
Wagner
John A
JA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001760:Bleeding Time; D003094:Collagen / Q000008:administration & dosage / Q000494:pharmacology; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000008:administration & dosage* / Q000494:pharmacology*; D010919:Placebos; D010974:Platelet Aggregation / Q000187:drug effects*; D012016:Reference Values; D012680:Sensitivity and Specificity; D055815:Young Adult
D003692:Delayed-Action Preparations; D007211:Indoles; C518174:MK-0524; D010919:Placebos; D009525:Niacin; D003094:Collagen