Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects

Abstract

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.

Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis

“…It has been speculated that antagonism of DP1 could block the ability of endogenous PGD 2 to inhibit further platelet aggregation and thereby may indirectly enhance the reactivity of platelets. However, several clinical studies have indicated that treatment with the DP1 antagonist laropiprant has no platelet-aggregatory effect; in fact, a transient and mild increase in bleeding time has been reported (32)(33)(34). One caveat in interpreting this observation is that laropiprant has been shown to antagonize both DP1 and TP in humans (32)(33)(34), unlike the DP1-specifi c antagonist L-655 used in this mouse work.…”

“…However, several clinical studies have indicated that treatment with the DP1 antagonist laropiprant has no platelet-aggregatory effect; in fact, a transient and mild increase in bleeding time has been reported (32)(33)(34). One caveat in interpreting this observation is that laropiprant has been shown to antagonize both DP1 and TP in humans (32)(33)(34), unlike the DP1-specifi c antagonist L-655 used in this mouse work. Therefore, it is likely that the mild anti-platelet effects in humans are a result of TP antagonism and theoretically represent a net effect of antagonizing both DP1 and TP on platelets.…”

The effects of laropiprant on the antiplatelet activity of co-administered clopidogrel and aspirin

“…The same patient may appear in more than one category. volunteers, using a highly sensitive ex vivo method [12]. The results demonstrated that the platelet aggregation in response to increasing concentrations of collagen at 24 hours post-dose on day 7 was similar following treatment with either extended release nicotinic acid/laropiprant or extended release nicotinic acid alone [12].…”

“…volunteers, using a highly sensitive ex vivo method [12]. The results demonstrated that the platelet aggregation in response to increasing concentrations of collagen at 24 hours post-dose on day 7 was similar following treatment with either extended release nicotinic acid/laropiprant or extended release nicotinic acid alone [12]. At 2 hours post-dose on day 7, the EC 50 for collagen-induced platelet aggregation was $2-fold higher in the presence of laropiprant, suggesting an effect of laropiprant to inhibit platelet responsiveness to collagen [12].…”

“…A recent study demonstrated that laropiprant, administered alone or in combination with extended release nicotinic acid, produced no clinically meaningful effect on platelet reactivity as assessed by collagen-induced platelet aggregation and bleeding time in healthy participants [12]. Another report of two clinical studies conducted in healthy participants [13] evaluated the effects of laropiprant on the antiplatelet activity of clopidogrel or aspirin, two commonly used antiplatelet agents with different mechanisms of action [6,14].…”