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

Abstract

Laropiprant is an antagonist of the prostaglandin PGD2 receptor DP1. Laropiprant has a weak affinity for the thromboxane A2 receptor TP. Two double-blinded, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose laropiprant at steady state on the antiplatelet effects of multiple-dose aspirin and clopidogrel. Study 1 had two treatment periods, in which each healthy subject received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 80 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 80 mg (Treatment B) once daily for 7 days. Study 2 consisted of three treatment periods. In the first two, each patient with hypercholesterolemia or mixed dyslipidemia received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 81 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 81 mg (Treatment B) once daily for 7 days. In period 3, patients received a single dose of two tablets of extended release nicotinic acid 1 g/laropiprant 20 mg (Treatment C). In both studies, pharmacodynamic endpoints included bleeding time at 24 (primary) and 4 hours (secondary) post-dose following 7 days of once-daily laropiprant in combination with clopidogrel and aspirin, and platelet aggregation in platelet-rich plasma at 4 and 24 hours post-dose on day 7 (secondary). After 7 days, increased bleeding time of 27% (Study 1) and 23% (Study 2) at 24 hours post-dose was observed with laropiprant compared to placebo (both combined with clopidogrel and aspirin), with corresponding upper bounds of the 90% CI marginally exceeding the prespecified upper comparability bound of 1.50 in both studies. The GMR and 90% CI for bleeding time of laropiprant compared to placebo (both combined with clopidogrel and aspirin) at 4 hours post-dose on day 7 was 0.92 (0.70, 1.21) in Study 1, and 1.46 (1.20, 1.78) in Study 2. Compared with placebo, laropiprant (both combined with clopidogrel and aspirin) increased the inhibition of collagen- and ADP-induced platelet aggregation, respectively, by ∼2.4% and ∼8.1% in Study 1 and by ∼4% and ∼5.4% in Study 2, at 24 hours post-dose on day 7. The inhibition of collagen- and ADP-induced platelet aggregation, respectively, was increased by ∼0.1% and ∼5.0% in Study 1, and by ∼5% and ∼12% in Study 2, at 4 hours post-dose on day 7. In conclusion, co-administration of multiple doses of laropiprant with aspirin and clopidogrel induced a prolongation of bleeding time and an inhibitory effect on platelet aggregation ex vivo in healthy subjects and patients with dyslipidemia.

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database

“…In almost 40% of ICSRs, concomitant medications, especially acetylsalicylic acid, ezetimibe, levothyroxine, clopidogrel, atorvastatin and rosuvastatin, were reported. These data are not surprising considering that diseases for which those drugs are used are quite common in patients with hypercholesterolaemia, for whom multiple pharmacological treatments are frequently planned [53][54][55][56][57][58][59][60]. Therefore, the role of these concomitant medications in the occurrence of neuropsychiatric ADRs could not be excluded.…”

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part I: Alternative Niacin Regimens

“…Disconcertingly, laropiprant absent niacin inhibits platelet responsiveness to collagen and enhances the antiplatelet effects of aspirin and clopidogrel [ 48 , 49 ]. Accordingly, changes in platelet function in silico translated to prolonged bleeding time in vivo among dyslipidemics exposed to laropiprant absent niacin.…”

“…Accordingly, changes in platelet function in silico translated to prolonged bleeding time in vivo among dyslipidemics exposed to laropiprant absent niacin. Indeed, bleeding time was underestimated because the protocol censored the maximal bleeding time, but laropiprant-exposed subjects were still bleeding when they reached the contrived maximum [ 48 ]. Hence, laropiprant’s penchant to prolong bleeding implicates the novel chemical entity in the serious bleeding events in HPS2-THRIVE.…”