title: 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.
authors.affiliation: Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Hideo
authors.initials: H
authors.lastname: Naganuma
authors.forename: John T
authors.initials: JT
authors.lastname: Brandt
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushima
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
authors.forename: Stephen
authors.initials: S
authors.lastname: Freestone
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride