Abstract
Introduction Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ3 antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ3 antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. Standard light transmission aggregometry (LTA) is difficult to perform during STEMI, so we applied VerifyNow (VN) assays to assess the pharmacodynamics of RUC-4 relative to aspirin and ticagrelor. Methods Blood from healthy volunteers was anticoagulated with phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) or sodium citrate, treated in vitro with RUC-4, aspirin, and/or ticagrelor, and tested with the VN ADP + PGE 1 , iso-TRAP, and base channel (high concentration iso-TRAP + PAR-4 agonist) assays. The results were correlated with both ADP (20 µM)-induced LTA and flow cytometry measurement of receptor occupancy and data from individuals treated in vivo with RUC-4. Results RUC-4 inhibited all three VN assays, aspirin did not affect the assays, and ticagrelor markedly inhibited the ADP + PGE 1 assay, slightly inhibited the iso-TRAP assay, and did not inhibit the base channel assay. RUC-4's antiplatelet effects were potentiated in citrate compared with PPACK. Cut-off values were determined to correlate the results of the VN iso-TRAP and base channel assays with 80% inhibition of LTA. Conclusion The VN assays can differentiate the early potent anti-αIIbβ3 effects of RUC-4 from delayed effects of P2Y12 antagonists in the presence of aspirin. These pharmacodynamic assays can help guide the clinical development of RUC-4 and potentially be used to monitor RUC-4's effects in clinical practice.
Highlights
Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ[3] antagonists improves clinical outcomes, but they are difficult to use in prehospital settings
We studied the effects of different anticoagulants and aspirin on the results, and compared the data with a measure of receptor occupancy based on competitive binding of RUC-4 and the activation-dependent monoclonal antibody PAC1.41 we compared these data to those from patients with stable coronary artery disease on aspirin enrolled in the Phase 1 study, who had measurements of their ADP-induced platelet aggregation by light transmission aggregometry (LTA) using phenylalanyl-prolylarginyl chloromethyl ketone (PPACK)-anticoagulated blood
The antiplatelet effect of aspirin in the 6 participants who were taking aspirin was confirmed with the VN Aspirin assay, with those taking aspirin having values of 401–435 reaction units, all of which are below the cut-off value of 550 reaction units and consistent with aspirin-induced inhibition of platelet function, and those not taking aspirin having values of 670-771
Summary
Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ[3] antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ[3] antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. There is a need in the prehospital therapy of STEMI20 for a rapidly acting αIIbβ[3] antagonist that can be administered subcutaneously (SC) and rapidly achieve high-grade inhibition of platelet function. To decrease the hemorrhagic risk, it would be desirable for the drug’s antiplatelet effects to diminish as the antiplatelet effects of the commonly co-administered oral P2Y12 antagonists reach their maximal effects
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