A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Abstract

AimsThis double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. MethodsThirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. ResultsInhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 mm) ADP was significantly higher in the prasugrel 10 mg group (58.2 Ϯ 4.9% vs. 9.2 Ϯ 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 Ϯ 6.8% vs. 9.2 Ϯ 4.0%, P = 0.78). With 5 mm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 Ϯ 4.7%; clopidogrel 75 mg, 36.5 Ϯ 9.0%; vs. placebo, 11.3 Ϯ 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 Ϯ 252 s vs. placebo, 221 Ϯ 38 s, P = 0.05) but not with clopidogrel (283 Ϯ 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. ConclusionsCompared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.

Pharmacodynamic Comparisons for Single Loading Doses of Prasugrel (30mg) and Clopidogrel (600mg) in Healthy Korean Volunteers

“…13-15 Preclinical studies indicate that prasugrel is approximately 10-fold more potent than clopidogrel at inhibiting platelet aggregation, inhibiting thrombus formation and prolonging bleeding times. 16 The benefit of prasugrel relative to clopidogrel, however, can be accompanied by a higher risk of major bleeding. The large TRITON-TIMI 38 study provided the first conclusive evidence that prasugrel is associated with excess bleeding relative to clopidogrel (2.4% vs. 1.8%, P=0.03).…”

Oral Antiplatelet Therapy for the Management of Acute Coronary Syndromes: Defining the Role of Prasugrel

“…40,43,44 However, the phase III trial (TRI-TON-TIMI 38) revealed from the post hoc subgroup analysis that certain populations were at higher risk for adverse outcomes from prasugrel therapy. 33,34 Because of the lack of proven clinical benefit, patients 75 years old or older should not receive prasugrel unless they are at high risk for cardiovascular disease (diabetes or previous history of myocardial infarction).…”

Prasugrel as Antiplatelet Therapy in Patients With Acute Coronary Syndromes or Undergoing Percutaneous Coronary Intervention

“…Because of its chemical structure, prasugrel is efficiently converted to its active metabolite and is less dependent on specific cytochrome P450 enzymes for activation than is clopidogrel. 33 …”

“…13 Prasugrel is a novel agent in the thienopyridine class. Results of several studies [31][32][33][34][35][36][37] indicate that prasugrel has a faster onset of action, achieves higher levels of inhibition of platelet aggregation (see Figure), 31 and is associated with less interindividual variability than is clopidogrel. Because of its chemical structure, prasugrel is efficiently converted to its active metabolite and is less dependent on specific cytochrome P450 enzymes for activation than is clopidogrel.…”