The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite

Abstract

The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrelÕs active metabolite. J Thromb Haemost 2007; 5: 1545-51.Summary. Background and methods: Prasugrel is a novel orally active thienopyridine prodrug with potent and longlasting antiplatelet effects. Platelet inhibition reflects inhibition of P2Y 12 receptors by its active metabolite (AM). Previous studies have shown that the antiplatelet potency of prasugrel is at least 10 times higher than that of clopidogrel in rats and humans, but the mechanism of its higher potency has not yet been fully elucidated. Results: Oral administration of prasugrel to rats resulted in dose-related and time-related inhibition of ex vivo platelet aggregation, and its effect was about 10 times more potent than that of clopidogrel. The plasma concentration of prasugrel AM was higher than that of clopidogrel AM despite tenfold higher doses of clopidogrel, indicating more efficient in vivo production of prasugrel AM than of clopidogrel AM. In rat platelets, prasugrel AM inhibited in vitro platelet aggregation induced by adenosine 5¢-diphosphate (ADP) (10 lM) with an IC 50 value of 1.8 lM. Clopidogrel AM similarly inhibited platelet aggregation with an IC 50 value of 2.4 lM. Similar results were also observed for ADP-induced (10 lM) decreases in prostaglandin E 1 -stimulated rat platelet cAMP levels. These results indicate that both AMs have similar in vitro antiplatelet activities. Conclusions: The greater in vivo antiplatelet potency of prasugrel as compared to clopidogrel reflects more efficient in vivo generation of its AM, which demonstrates similar in vitro activity to clopidogrel AM.

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12receptorsin vitro

“…The data suggests that prasugrel AM may be better able to compete with cangrelor than clopidogrel AM despite both thienopyridine AMs having similar IC 50 values (0.30 mol/L) [16].…”

Current Oral Antiplatelets: Focus Update on Prasugrel

“…5 Prasugrel, a novel thienopyridine, has been shown to have faster and more complete antiplatelet action in vivo compared with other thienopyridines. 13 It also has lesser inter patient variability in its antiplatelet effects when compared with clopidogrel. These desirable effects are because of better absorption and a more efficient metabolism.…”

“…Prasugrel is approximately 10-and 100-fold more potent in inhibiting platelet function in vivo than clopidogrel and ticlopidine, respectively. 13 A 60-mg loading dose of prasugrel followed by a 10-mg daily maintenance dose resulted in greater level of inhibition of platelet aggregation at 4 hours compared with a 300-mg loading dose of clopidogrel with a 75-mg daily maintenance dose (68.4% vs 30%, respectively). In addition, the pharmacologic nonresponders were fewer with prasugrel compared with clopidogrel (3% vs 52%, respectively).…”

Cangrelor for the management and prevention of arterial thrombosis

“…Similarly, the ability of prasugrel to provide platelet inhibition is sensitive to the timing of its administration relative to cangrelor infusion such that it is recommended that prasugrel loading dose is administered 30 minutes before the cessation of cangrelor infusion [42]. This is because of two key considerations: (1) the distribution half-lives of both clopidogrel and prasugrel active metabolites are short (30 to 60 minutes) so that therapeutic levels of the active metabolites decline rapidly following absorption and metabolism of the parent drug [43][44][45][46]; and (2) these active metabolites are unable to bind to the platelet P2Y 12 receptor whilst cangrelor is bound to the receptor [47,48]. Consequently, if the levels of the active metabolites fall to subtherapeutic concentrations before cangrelor has dissociated from the platelet P2Y 12 receptors then no effective platelet inhibition will ensue.…”