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CC BY 4.0 · TH Open 2021; 05(03): e449-e460
DOI: 10.1055/s-0041-1732343
Original Article

Application of Auxiliary VerifyNow Point-of-Care Assays to Assess the Pharmacodynamics of RUC-4, a Novel αIIbβ3 Receptor Antagonist

Ohad S. Bentur 
1   Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York, United States
,
Jihong Li
1   Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York, United States
,
Caroline S. Jiang
2   The Rockefeller University Hospital, New York, New York, United States
,
Linda H. Martin
3   The Carl and Edyth Lindner Center for Research and Education at the Christ Hospital, Cincinnati, Ohio, United States
,
Dean J. Kereiakes
3   The Carl and Edyth Lindner Center for Research and Education at the Christ Hospital, Cincinnati, Ohio, United States
,
Barry S. Coller
1   Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York, United States
› Author Affiliations Funding B.S.C is supported by grant 19278 from the National Heart, Lung and Blood Institute and funds from Stony Brook University. B.S.C and O.S.B are supported by grant UL1 TR001866 from the National Center for Advancing Translational Sciences, National Institutes of Health. The RUC-4 Phase I study was funded by CeleCor Therapeutics. CeleCor Therapeutics supplied RUC-4, the VerifyNow assay instrument and the cartridges and tubes used in this study.
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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 + PGE1, 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 + PGE1 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.

Keywords

STEMI - platelet aggregation inhibitors - point-of-care testing - platelet glycoprotein GPIIb-IIIa complex - acute myocardial infarction

Author Contributions

O. S. Bentur contributed concept/design, designed, and conducted the in vitro experiments, analyzed the data, drafted the article, and critically revised the article. J. Li designed and provided training on the PAC1 binding assay. C. S. Jiang analyzed and interpreted the data. L. H. Martin participated in the planning and carrying out of the phase I study. D. J. Kereiakes was the principal investigator of the RUC-4 phase I study and critically reviewed the article. B. S. Coller conceived and oversaw the project, drafted the article, critically revised the article, and approved the article.


Supplementary Material



Publication History

Received: 28 January 2021

Accepted: 16 June 2021

Article published online:
28 September 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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