Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction.
Journal
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
ISSN: 1969-6213
Titre abrégé: EuroIntervention
Pays: France
ID NLM: 101251040
Informations de publication
Date de publication:
06 Aug 2021
06 Aug 2021
Historique:
pubmed:
26
5
2021
medline:
11
8
2021
entrez:
25
5
2021
Statut:
epublish
Résumé
Pre-hospital platelet inhibition in patients with ST-segment elevation myocardial infarction (STEMI) may improve outcomes. RUC-4 is a novel, second-generation glycoprotein IIb/IIIa inhibitor designed for first-point-of-medical-contact treatment for STEMI by subcutaneous injection. The open-label, phase 2A, CEL-02 trial aimed to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI (pPCI). A total of 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before pPCI in escalating doses (0.075 mg/kg [n=8], 0.090 mg/kg [n=9], or 0.110 mg/kg [n=10]). The primary PD endpoint of high-grade (≥77%) inhibition of the VerifyNow iso-TRAP assay at 15 minutes was met in 3/8, 7/8, and 7/8 patients in the three cohorts with a dose-response relationship (mean inhibition [min - max] of 77.5% [65.7%-90.6%], 87.5% [73.8%-93.1%], and 91.7% [76.4%-99.3%], respectively; ptrend=0.002). Fifty percent (50%) inhibition remained after 89.1 (38.0-129.7), 104.2 (17.6-190.8), and 112.4 (19.7-205.0) minutes. Injection site reactions or bruising were observed in 1 (4%) and 11 (41%) patients, respectively. Mild access-site haematomas occurred in 6 (22%), and severe access-site haematomas occurred in 2 patients (7%). No thrombocytopaenia was observed within 72 hours post dose. In patients with STEMI, a single subcutaneous dose of RUC-4 at 0.075, 0.090, and 0.110 mg/kg showed dose-response high-grade inhibition of platelet function within 15 minutes.
Sections du résumé
BACKGROUND
BACKGROUND
Pre-hospital platelet inhibition in patients with ST-segment elevation myocardial infarction (STEMI) may improve outcomes. RUC-4 is a novel, second-generation glycoprotein IIb/IIIa inhibitor designed for first-point-of-medical-contact treatment for STEMI by subcutaneous injection.
AIMS
OBJECTIVE
The open-label, phase 2A, CEL-02 trial aimed to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI (pPCI).
METHODS
METHODS
A total of 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before pPCI in escalating doses (0.075 mg/kg [n=8], 0.090 mg/kg [n=9], or 0.110 mg/kg [n=10]).
RESULTS
RESULTS
The primary PD endpoint of high-grade (≥77%) inhibition of the VerifyNow iso-TRAP assay at 15 minutes was met in 3/8, 7/8, and 7/8 patients in the three cohorts with a dose-response relationship (mean inhibition [min - max] of 77.5% [65.7%-90.6%], 87.5% [73.8%-93.1%], and 91.7% [76.4%-99.3%], respectively; ptrend=0.002). Fifty percent (50%) inhibition remained after 89.1 (38.0-129.7), 104.2 (17.6-190.8), and 112.4 (19.7-205.0) minutes. Injection site reactions or bruising were observed in 1 (4%) and 11 (41%) patients, respectively. Mild access-site haematomas occurred in 6 (22%), and severe access-site haematomas occurred in 2 patients (7%). No thrombocytopaenia was observed within 72 hours post dose.
CONCLUSIONS
CONCLUSIONS
In patients with STEMI, a single subcutaneous dose of RUC-4 at 0.075, 0.090, and 0.110 mg/kg showed dose-response high-grade inhibition of platelet function within 15 minutes.
Identifiants
pubmed: 34031019
pii: EIJ-D-21-00287
doi: 10.4244/EIJ-D-21-00287
pmc: PMC9464482
mid: NIHMS1832375
pii:
doi:
Substances chimiques
Platelet Aggregation Inhibitors
0
Platelet Glycoprotein GPIIb-IIIa Complex
0
Types de publication
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e401-e410Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL019278
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Références
Blood. 2012 Jun 28;119(26):6317-25
pubmed: 22490676
JACC Cardiovasc Interv. 2015 Oct;8(12):1574-82
pubmed: 26493250
Int J Cardiol. 2013 Jan 20;162(3):210-9
pubmed: 22769575
Cochrane Database Syst Rev. 2013 Oct 18;(10):CD002130
pubmed: 24136036
J Am Heart Assoc. 2020 Sep;9(17):e016552
pubmed: 32844723
Thromb Haemost. 2016 Aug 1;116(2):369-78
pubmed: 27196998
Eur Heart J. 2018 Jan 14;39(3):213-260
pubmed: 28886622
Sci Transl Med. 2012 Mar 14;4(125):125ra32
pubmed: 22422993
J Am Coll Cardiol. 2010 Jun 1;55(22):2446-55
pubmed: 20510211
J Am Coll Cardiol. 2015 Feb 10;65(5):511-2
pubmed: 25660931
Circulation. 2019 Apr 2;139(14):1661-1670
pubmed: 30630341
Am J Cardiol. 2009 Dec 15;104(12):1638-40
pubmed: 19962467
Platelets. 2011;22(8):619-25
pubmed: 21639823
Lancet. 2015 Jun 20;385(9986):2465-76
pubmed: 25791214
Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2321-9
pubmed: 25147334
Circulation. 2020 Aug 4;142(5):441-454
pubmed: 32795098
Eur Heart J Cardiovasc Pharmacother. 2015 Apr;1(2):97-106
pubmed: 27533978
Lancet. 2008 Aug 16;372(9638):537-46
pubmed: 18707985
J Am Coll Cardiol. 2020 May 26;75(20):2588-2597
pubmed: 32439008
Eur Heart J. 2018 Jan 7;39(2):119-177
pubmed: 28886621
J Interv Cardiol. 2002 Feb;15(1):45-60
pubmed: 12053684
J Clin Transl Sci. 2019 Jun;3(2-3):65-74
pubmed: 31544007
Circulation. 2020 Dec 15;142(24):2316-2328
pubmed: 33315489
J Am Coll Cardiol. 2016 May 3;67(17):1994-2004
pubmed: 27012781
J Biol Chem. 1993 Oct 5;268(28):20741-3
pubmed: 8104935
J Thromb Haemost. 2011 Dec;9(12):2361-70
pubmed: 21929513
J Am Coll Cardiol. 2013 Apr 16;61(15):1601-6
pubmed: 23500251
Thromb Haemost. 2016 Jan;115(1):213-21
pubmed: 26581884
JACC Cardiovasc Interv. 2015 Sep;8(11):1457-1467
pubmed: 26404199
Circulation. 2011 Jun 14;123(23):2736-47
pubmed: 21670242