Abstract Number: PB1466
Meeting: ISTH 2020 Congress
Background: Selatogrel represents a new chemical class of reversibly-binding P2Y12 receptor (P2Y12R) antagonists, which is being developed for subcutaneous administration in patients with acute coronary syndrome.
Aims: To characterize the potency of selatogrel in vitro with recombinant P2Y12R and with assay systems commonly used in the clinic.
Methods: Potency of selatogrel was profiled using radioligand (3H-Selatogrel) binding with recombinant P2Y12R. We performed light transmission aggregation (LTA) with human platelet rich plasma (PRP) and VerifyNow® aggregation with human blood in vitro.
Results: Radioligand binding in the presence of increasing ADP concentrations verified that selatogrel is a competitive antagonist of ADP-binding to P2Y12R. Selatogrel potency was comparable between LTA and VerifyNow®. The method of anticoagulation affected the potency of selatogrel. Using citrated blood (i.e. low calcium concentration), the potency of selatogrel was reduced 3 fold relative to blood anticoagulated with a direct thrombin inhibitor, which preserves physiologic calcium concentration. Similar potency shifts were observed for the reversible P2Y12 antagonists ticagrelor, cangrelor and elinogrel. Radioligand binding experiments confirmed that low calcium concentration reduced binding affinity of 3H-Selatogrel to P2Y12R. In addition, ADP stimulation of platelets at low calcium concentration resulted in a higher maximal extent of platelet aggregation, increased alpha granule secretion and elevated GPIIb-IIIa receptor surface expression relative to conditions with physiological calcium concentrations.
Conclusions: Selatogrel is a potent and reversible antagonist of P2Y12R. Radioligand binding experiments confirmed that selatogrel prevents ADP binding to P2Y12R. In functional platelet assays at low calcium concentration, the potency of selatogrel was reduced due to lower P2Y12R binding affinity and increased platelet response to ADP. To avoid underestimation of reversible P2Y12R antagonist potency and thus recommendation of a supratherapeutic dosing regimen, clinical profiling of reversible P2Y12R antagonists should be performed in blood containing physiological calcium concentrations.
To cite this abstract in AMA style:Baumann M, Riederer MA. Method of Anticoagulation Influences Potency of Reversible P2Y12 Receptor Antagonists [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/method-of-anticoagulation-influences-potency-of-reversible-p2y12-receptor-antagonists/. Accessed August 15, 2022.
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