Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y₁₂ inhibitor: A single ascending dose study in healthy humans

Abstract

We assessed the tolerability, pharmacodynamics as measured by inhibition of platelet aggregation (IPA), and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent in healthy volunteers. Twenty-four subjects were randomized into four groups of six in a double-blind, placebo-controlled trial. One subject in each group received placebo and five subjects received prasugrel orally at single doses of 2.5, 10, 30, or 75 mg. The IPA, assessed using 5 and 20 microM ADP, was periodically measured over a 7-day period by light transmission aggregometry. Plasma concentrations for three major metabolites, R-95913, R-106583, and R-100932, were measured. There were no serious adverse events and no clinically significant changes noted in any laboratory or clinical evaluations in any subject. At 1 h after prasugrel 30 and 75 mg, platelet aggregation induced by 20 microM ADP was inhibited by 43.5 +/- 7.8 and 43.2 +/- 15.7%, respectively, and this inhibition was significantly greater than that following placebo (5.9 +/- 3.5%) (P < 0.05 for both doses). The degree of inhibition observed at 2 h was slightly higher with both prasugrel 30 and 75 mg (59.8 +/- 9.9 and 57.0 +/- 7.2%) and was maintained through the subsequent 22 h. At 24 h, maximal platelet aggregation induced by 20 microM ADP was reduced to <or=39% in all subjects receiving prasugrel 30 mg and to <or=38% in subjects receiving prasugrel 75 mg. Full recovery of platelet aggregation occurred between 48 h and 7 days suggesting irreversible inhibition by prasugrel and/or its metabolites. With prasugrel 2.5 and 10 mg, there was no measurable effect on platelet aggregation throughout the study (P > 0.05 for 2.5 and 10 mg prasugrel vs. placebo). With prasugrel 75 mg at 4 h postdose, there was a significant increase in the mean bleeding time compared to placebo (682 vs. 161 s; P < 0.05). Prasugrel metabolites obeyed linear pharmacokinetics and the three metabolites appeared in the plasma soon after administration, reaching maximum levels at approximately 1 h. In conclusion, prasugrel 30 and 75 mg were well tolerated and achieved a consistently high level of platelet inhibition with a fast onset of action.

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

“…The results for prasugrel are in agreement with previous studies of prasugrel [20,21] in healthy volunteers, but which did not include a clopidogrel comparison. Inhibition of platelet aggregation was greater with 10 and 20 mg prasugrel compared with clopidogrel 75 mg and the consistency of response to prasugrel was better than that observed with clopidogrel.…”

“…In total, 10 doses were given to each subject. Previous single and 10-day multiple oral dose studies [20,21] in healthy subjects have shown that prasugrel 10 mg daily was well tolerated and produced a measurable and sustained pharmacodynamic effect on inhibition of platelet aggregation. Clopidogrel 75 mg is the approved clinical dose for maintenance therapy.…”

“…More recently, a novel thienopyridine P2Y 12 inhibitor, prasugrel (CS-747, LY640315), has been identified and profiled [19][20][21][22][23]. Preclinical studies indicate that like clopidogrel, prasugrel is a prodrug that requires metabolic conversion to an active metabolite [19].…”

“…These early studies demonstrated that the dose required to achieve a given degree of platelet inhibition or inhibition of thrombus formation in preclinical models was approximately one-tenth and one-hundredth that of clopidogrel and ticlopidine, respectively. The potency, rapid onset of platelet inhibition, and cumulative degree of platelet inhibition with daily dosing of prasugrel were characterized in two early clinical studies evaluating single and multiple daily dosing of prasugrel in healthy volunteers [20,21]. These early studies, however, were limited by the absence of an active comparator such as clopidogrel.…”

Review of Prasugrel for the Secondary Prevention of Atherothrombosis

“…The pharmacokinetic properties of prasugrel and clopidogrel have been investigated in several studies and are summarized in Table 2. 12,[29][30][31][32][33][34][35][36][37][38][39][40][41][42] In contrast to clopidogrel, [43][44][45] genetic variants in CYP 2C19 genes have not been shown to affect the antiplatelet response to prasugrel. …”