Schilling Uta, Dingemanse Jasper, Ufer Mike
Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
Clin Pharmacokinet. 2020 May;59(5):545-566. doi: 10.1007/s40262-020-00864-4.
Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naïve patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug-drug interaction liability.
冠状动脉疾病仍然是全球范围内主要的死亡原因。抗血小板药物如乙酰水杨酸和P2Y12受体拮抗剂是预防冠状动脉疾病患者血栓形成事件的基础治疗药物。氯吡格雷长期以来一直是金标准，但存在主要的药理学局限性，如起效缓慢、作用持续时间长，以及血小板抑制作用较弱，个体间药代动力学和药效学变异性高。迫切需要开发具有更有利药理学特性的强效P2Y12受体拮抗剂。普拉格雷和替格瑞洛作用更强且起效更快；然而，与氯吡格雷相比，它们的出血风险增加。坎格雷洛效力很强，起效和作用消失都非常迅速；然而，其适应证仅限于未使用过P2Y12拮抗剂的接受经皮冠状动脉介入治疗的患者。目前有两种新型P2Y12受体拮抗剂正在进行临床开发，即维卡格雷和塞拉格雷。维卡格雷是氯吡格雷的类似物，其活性代谢产物的形成增强且更有效。塞拉格雷的特点是皮下给药后起效迅速，用于疑似急性心肌梗死的早期治疗。这篇综述文章描述了已上市的P2Y12受体拮抗剂以及正在开发的药物的临床药理学概况，重点关注药代动力学、药效学和药物相互作用情况。
