Comparison of ticagrelor and thienopyridine P2Y12 binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis

• Published in: Thrombosis research Vol. 124; no. 5; pp. 565 - 571
• Main Authors: van Giezen, J.J.J, Berntsson, Pia, Zachrisson, Helen, Björkman, Jan-Arne
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.11.2009
• Subjects: Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Hematology, Oncology and Palliative Medicine; Medical sciences; Pharmacology. Drug treatments; Vasodilator agents. Cerebral vasodilators; AZD6140; Thienopyridine; Platelet aggregation; Ticagrelor; Bleeding; P2Y 12; Fissipedia; Carnivora; Rat; Rodentia; Cardiovascular disease; Hemorrhage; Thrombosis; Antiplatelet agent; Vascular disease; Aggregation; Vertebrata; Platelet; Mammalia; Hemostasis; Animal; P2Y; Dog; Comparative study
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2009.06.029

Abstract Ticagrelor (AZD6140), the first reversibly binding oral P2Y12 receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y12 for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y12 and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y12 , and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets. In rat and dog models of thrombosis/hemostasis, there was greater separation between doses that provided antithrombotic effect and those that increased bleeding for ticagrelor compared with clopidogrel and compound 072, a chemical compound indistinguishable from the prasugrel parent compound. The ratio of dose resulting in 3-fold increase in bleeding time to dose resulting in 50% restoration of blood flow in rats was 9.7 for ticagrelor compared with 2.0 for clopidogrel and 1.4 for compound 072. Similar results were observed in dogs. Our findings suggest that reversibility of P2Y12 binding with ticagrelor may account for the greater separation between antithrombotic effects and increased bleeding compared with the irreversible binding of clopidogrel and prasugrel.