Department of Clinical Pharmacology, AstraZeneca LP, Wilmington, DE, USA.
J Clin Pharm Ther. 2012 Dec;37(6):704-11. doi: 10.1111/j.1365-2710.2012.01367.x. Epub 2012 Jul 2.
Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co-administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug-drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin.
In two open-label, three-period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti-factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured.
Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co-administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co-administration of enoxaparin, except for a marginal (-2.9%; 908.7%.h, 881.9%.h) reduction in final extent area under the effect curve (AUEC)(2-12) (95% CI: -51.6%.h, -2.0%.h). Co-administering UFH with ticagrelor caused small decreases in IPA(max) (-3.8%; 94.6%, 91.0%) and AUEC(2-12) (-6.8%; 888.6%.h, 828.3%.h) vs. ticagrelor alone (95% CI: final extent IPA(max) -5.7%, -1.6%; AUEC(2-12) -109.8%.h, -10.8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti-factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2).
Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.
患有急性冠状动脉综合征（ACS）的患者同时接受多种药物治疗，包括抗血小板和抗凝药物。由于未分级肝素（UFH）在体外和体内激活血小板，与抗血小板药物联合使用可能会降低后者的临床疗效。因此，目的是确定新型口服抗血小板药物替格瑞洛与 UFH 或依诺肝素之间是否存在任何潜在的药物相互作用。
在两项开放标签、三周期交叉试验中，健康受试者被随机分配接受替格瑞洛单药治疗或与依诺肝素（研究 1）或 UFH（研究 2）联合治疗，或依诺肝素或 UFH 单药治疗。测量替格瑞洛的血浆浓度、血小板聚集抑制（IPA）、抗因子 Xa 水平、活化部分凝血活酶时间（aPTT）和活化凝血时间（ACT）。
分别有 30 名和 28 名受试者完成了研究 1 和 2。研究药物总体耐受性良好，无明显出血或严重不良事件。依诺肝素或 UFH 联合使用对替格瑞洛的药代动力学无显著影响。替格瑞洛对 IPA 的影响不受依诺肝素联合使用的影响，除了最终效应曲线下面积（AUEC）（2-12）（95%CI：-51.6%.h，-2.0%.h）的边际降低（-2.9%；94.6%，881.9%。h）。与替格瑞洛单药治疗相比，替格瑞洛与 UFH 联合使用导致 IPA（max）（-3.8%；94.6%，91.0%）和 AUEC（2-12）（-6.8%；888.6%。h，828.3%。h）的降低（95%CI：IPA（max）最终程度-5.7%，-1.6%；AUEC（2-12）-109.8%。h，-10.8%。h）。替格瑞洛对依诺肝素的抗因子 Xa（研究 1）或 UFH 的 aPTT 或 ACT（研究 2）无临床显著影响。
依诺肝素和 UFH 对替格瑞洛的药代动力学无影响，对替格瑞洛的药效学无临床显著影响。替格瑞洛对依诺肝素或 UFH 的药效学无临床显著影响。
