Department of Bioscience, AstraZeneca R&D Mölndal, Sweden.
Thromb Res. 2012 Oct;130(4):622-8. doi: 10.1016/j.thromres.2012.07.021. Epub 2012 Aug 19.
As ticagrelor, clopidogrel and cangrelor therapies may be used in the same clinical setting, their potential pharmacodynamic interactions are of interest. Hence, we investigated possible interactions between these agents in dogs using a variety of switching protocols.
Six male dogs all received 7 different dosing regimens separated by 1-5week washout periods: cangrelor (1μg/kg/min, intravenous infusion); ticagrelor (0.8mg/kg, oral); clopidogrel (3mg/kg, intravenous injection); cangrelor together with ticagrelor initiated 10minutes after cangrelor infusion start or clopidogrel given 30minutes after cangrelor infusion start; ticagrelor followed by clopidogrel given 3 or 7hours after ticagrelor dosing. ADP-induced whole blood platelet aggregation was measured by impedance aggregometry.
Mean maximum inhibition of platelet aggregation (IPA) was 81-87% at 6minutes (cangrelor), 3hours (ticagrelor) and 4hours (clopidogrel) postdosing and platelet function recovered after 1.5hours, 12hours, and 9days, respectively. IPA at 2hours post clopidogrel was reduced to 39% when clopidogrel was given during cangrelor infusion versus 69% for clopidogrel alone. With clopidogrel dosed 3hours after ticagrelor, IPA was reduced after washout of ticagrelor to 38% at 24hrs vs. 68% for clopidogrel alone, but an interaction was not seen when clopidogrel was dosed 7hours after ticagrelor. No pharmacodynamic interaction occurred between ticagrelor and cangrelor.
The extent of the pharmacodynamic drug-drug interactions observed between clopidogrel and cangrelor or ticagrelor apparently depends on the level of receptor occupancy when clopidogrel is administered. Importantly, no significant pharmacodynamic interaction occurred between ticagrelor/clopidogrel when clopidogrel was given at clinical trough IPA levels with ticagrelor. No significant pharmacodynamic interaction occurred with cangrelor and ticagrelor.
替格瑞洛、氯吡格雷和坎格瑞洛的治疗可能在同一临床环境中使用，因此它们之间潜在的药效学相互作用很有意义。为此，我们使用各种转换方案研究了这些药物在犬中的可能相互作用。
六只雄性犬均接受了 7 种不同的给药方案，每种方案之间有 1-5 周的洗脱期：坎格瑞洛（1μg/kg/min，静脉输注）；替格瑞洛（0.8mg/kg，口服）；氯吡格雷（3mg/kg，静脉注射）；坎格瑞洛输注开始后 10 分钟给予替格瑞洛或氯吡格雷开始后 30 分钟给予坎格瑞洛；替格瑞洛后 3 或 7 小时给予氯吡格雷。采用阻抗聚集法测量 ADP 诱导的全血血小板聚集。
替格瑞洛给药后 6 分钟（坎格瑞洛）、3 小时（替格瑞洛）和 4 小时（氯吡格雷）的最大血小板聚集抑制率（IPA）平均值为 81-87%，1.5 小时、12 小时和 9 天后血小板功能恢复。与单独给予氯吡格雷相比，氯吡格雷在坎格瑞洛输注期间给予时，氯吡格雷给药后 2 小时的 IPA 降低至 39%。替格瑞洛给药后 3 小时给予氯吡格雷，替格瑞洛洗脱后 24 小时 IPA 降低至 38%，而单独给予氯吡格雷时 IPA 为 68%，但当替格瑞洛给药后 7 小时给予氯吡格雷时未观察到相互作用。替格瑞洛和坎格瑞洛之间未发生药效学相互作用。
观察到的氯吡格雷与坎格瑞洛或替格瑞洛之间药效学药物相互作用的程度显然取决于氯吡格雷给药时受体占有率的水平。重要的是，当氯吡格雷在替格瑞洛的临床谷 IPA 水平时给予时，替格瑞洛/氯吡格雷之间未发生显著的药效学相互作用。坎格瑞洛和替格瑞洛之间未发生显著的药效学相互作用。
