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Preclinical studies of RUC-4, a novel platelet αIIbβ3 antagonist, in non-human primates and with human platelets

  • Spandana Vootukuri (a1), Jihong Li (a1), Mark Nedelman (a2), Craig Thomas (a3) (a4), Jiang-Kang Jiang (a4), Mariana Babayeva (a5) and Barry S. Coller (a1)...

Abstract

Introduction:

We are developing the novel αIIbβ3 antagonist, RUC-4, for subcutaneously (SC)-administered first-point-of-medical-contact treatment for ST segment elevation myocardial infarction (STEMI).

Methods:

We studied the (1) pharmacokinetics (PK) of RUC-4 at 1.0, 1.93, and 3.86 mg/kg intravenous (IV), intramuscular (IM), and SC in non-human primates (NHPs); (2) impact of aspirin on RUC-4 IC50 in human platelet-rich plasma (PRP); (3) effect of different anticoagulants on the RUC-4 IC50 in human PRP; and (4) relationship between αIIbβ3 receptor blockade by RUC-4 and inhibition of ADP-induced platelet aggregation.

Results:

(1) All doses of RUC-4 were well tolerated, but animals demonstrated variable temporary bruising. IM and SC RUC-4 reached dose-dependent peak levels within 5–15 minutes, with T1/2 s between 0.28 and 0.56 hours. Platelet aggregation studies in NHPs receiving IM RUC-4 demonstrated >80% inhibition of the initial slope of ADP-induced aggregation with all three doses 30 minutes post-dosing, with subsequent dose-dependent loss of inhibition over 4–5 hours. (2) The RUC-4 IC50 for ADP-induced platelet aggregation was unaffected by aspirin treatment (40±9 nM vs 37±5 nM; p = 0.39). (3) The RUC-4 IC50 was significantly higher in PRP prepared from D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK)-anticoagulated blood compared to citrate-anticoagulated blood using either thrombin receptor activating peptide (TRAP) (122±17 vs 66±25 nM; p = 0.05; n = 4) or ADP (102±22 vs 54±13; p<0.001; n = 5). (4) There was a close correspondence between receptor blockade and inhibition of ADP-induced platelet aggregation, with aggregation inhibition beginning with ~40% receptor blockade and becoming nearly complete at >80% receptor blockade.

Discussion:

Based on these results and others, RUC-4 has now progressed to formal preclinical toxicology studies.

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Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.

Corresponding author

Address for correspondence: B. S. Coller, MD, Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Email: collerb@rockefeller.edu

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Keywords

Preclinical studies of RUC-4, a novel platelet αIIbβ3 antagonist, in non-human primates and with human platelets

  • Spandana Vootukuri (a1), Jihong Li (a1), Mark Nedelman (a2), Craig Thomas (a3) (a4), Jiang-Kang Jiang (a4), Mariana Babayeva (a5) and Barry S. Coller (a1)...

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