Asai Fumitoshi, Jakubowski Joseph A, Naganuma Hideo, Brandt John T, Matsushima Nobuko, Hirota Takashi, Freestone Stephen, Winters Kenneth J
Sankyo Co., Ltd., Tokyo, Japan.
Platelets. 2006 Jun;17(4):209-17. doi: 10.1080/09537100600565551.
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.
我们评估了新型噻吩并吡啶类抗血小板药物普拉格雷（CS - 747，LY640315）在健康志愿者中的耐受性、通过抑制血小板聚集（IPA）测定的药效学以及药代动力学。在一项双盲、安慰剂对照试验中，24名受试者被随机分为四组，每组6人。每组一名受试者接受安慰剂，五名受试者分别口服2.5、10、30或75 mg单剂量的普拉格雷。使用5和20 microM ADP评估的IPA，在7天时间内通过光透射聚集法定期测量。测定了三种主要代谢物R - 95913、R - 106583和R - 100932的血浆浓度。在任何受试者的任何实验室或临床评估中均未发现严重不良事件，也未观察到具有临床意义的变化。服用30和75 mg普拉格雷后1小时，20 microM ADP诱导的血小板聚集分别被抑制43.5±7.8%和43.2±15.7%，这种抑制作用显著大于安慰剂组（5.9±3.5%）（两种剂量均P<0.05）。服用30和75 mg普拉格雷后2小时观察到的抑制程度略高（分别为59.8±9.9%和57.0±7.2%），并在随后的22小时内保持。在24小时时，所有接受30 mg普拉格雷的受试者中，20 microM ADP诱导的最大血小板聚集降低至≤39%，接受75 mg普拉格雷的受试者中降低至≤38%。血小板聚集在48小时至7天之间完全恢复，提示普拉格雷及其代谢物具有不可逆抑制作用。服用2.5和10 mg普拉格雷时，在整个研究过程中对血小板聚集没有可测量的影响（2.5和10 mg普拉格雷与安慰剂相比P>0.05）。服用75 mg普拉格雷后4小时，与安慰剂相比平均出血时间显著延长（分别为682秒和161秒；P<0.05）。普拉格雷代谢物符合线性药代动力学，三种代谢物在给药后很快出现在血浆中，在大约1小时达到最高水平。总之，30和75 mg普拉格雷耐受性良好，起效迅速，能持续达到较高水平的血小板抑制作用。
