Dose-Dependent Inhibition of Human Platelet Aggregation by Prasugrel and its Interaction With Aspirin in Healthy Subjects

Abstract

The aims of this open-label, randomized, dose-escalation pharmacodynamic study of prasugrel, an orally active antiplatelet agent, were to assess its interaction with aspirin (ASA, 325 mg) in healthy subjects after a loading dose (LD) and subsequent 5 days of once-daily maintenance doses (MD) of prasugrel or the active comparator, clopidogrel. We measured platelet aggregation induced by ADP, collagen, and TRAP and compared effects on maximal and residual platelet aggregation responses. On a background of ASA, subjects were randomly assigned to 1 of 4 prasugrel treatment groups (LD/MD in mg: 20/5, 30/7.5, 40/10, or 60/15; n = 8/group) or to clopidogrel 300 mg LD/75 mg MD (n = 11). Prasugrel dosedependently inhibited ADP-induced platelet aggregation and exhibited higher levels of platelet inhibition than clopidogrel or ASA alone. Prasugrel plus ASA resulted in additive inhibition of collagenand TRAP-induced platelet aggregation. Although inhibition of residual aggregation was greater than inhibition of maximal aggregation, values were highly correlated. The safety and tolerability of prasugrel plus ASA were also monitored. Within the limitations of the study, prasugrel was found to be well tolerated when dosed as LD followed by MD in the presence of ASA and provided greater platelet inhibition than ASA alone.

Studies on the role of the extracellular cysteines and oligomeric structures of the P2Y12 receptor when interacting with antagonists

“…Thus, any agent antagonizing either of these receptors is expected to inhibit platelet activation and hence can be used as an antithrombotic drug. Clopidogrel [2][3][4] and prasugrel [5,6] are thienopyridine antithrombotic drugs, metabolized in the liver to active metabolites that irreversibly antagonize the platelet P2Y 12 receptor. AR-C69931MX, also known as Cangrelor, is a reversible P2Y 12 antagonist [7].…”

Antiplatelet Agents

“…These studies also indicated that there was a 60-fold greater exposure of the active metabolite of prasugrel than the active metabolite of clopidogrel, on a dose-adjusted basis [249]. In combination with aspirin (325 mg) prasugrel showed a 60% inhibition of platelet aggregation 2-6 h after a loading dose of 60 mg, whereas a 300 mg loading dose of clopidogrel gave 35% inhibition under similar conditions [250].…”

Prasugrel: A novel antiplatelet agent

“…Jakubowski et al 19 assessed the use of a prasugrel loading dose and daily maintenance dose regimen at varying dosage ranges versus a clopidogrel loading dose and daily maintenance dose regimen over a five-day period in healthy adults in an open-label, randomized trial. Study endpoints included platelet aggregation, bleeding time, and adverse effects.…”