Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial

Georg Gelbenegger; Juergen Grafeneder; Gloria M Gager; Jolanta M Siller-Matula; Michael Schwameis; Bernd Jilma; Christian Schoergenhofer

doi:10.1186/s12959-022-00377-z

Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial

Thromb J. 2022 Apr 14;20(1):19. doi: 10.1186/s12959-022-00377-z.

Authors

Georg Gelbenegger¹, Juergen Grafeneder², Gloria M Gager^{1

3}, Jolanta M Siller-Matula^{3

4}, Michael Schwameis², Bernd Jilma¹, Christian Schoergenhofer⁵

Affiliations

¹ Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
² Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
³ Department of Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
⁴ Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, Warsaw, Poland.
⁵ Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. christian.schoergenhofer@meduniwien.ac.at.

Abstract

Background: High on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers.

Methods: We conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P) and the platelet function analyzer. In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor.

Results: All cangrelor bolus infusions resulted in immediate and pronounced platelet inhibition. Bolus infusions of cangrelor 20 mg resulted in sufficient platelet inhibition assessed by MEA for 20 min in 90% of subjects. Infusion of cangrelor via the IV flow regulator resulted in sufficient platelet inhibition throughout the course of administration. Ex vivo epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner.

Conclusions: Weight-adapted bolus infusions followed by a continuous infusion of cangrelor via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as weight-adapted bolus infusion followed by a continuous infusion using an IV flow regulator may be a viable treatment approach for effective and well controllable prehospital platelet inhibition.

Trial registration: EC (Medical University of Vienna) 1835/2019 and EudraCT 2019-002792-34 .

Keywords: Cangrelor; Myocardial infarction; P2Y12; Pharmacodynamics; Platelet inhibition; Prehospital; STEMI.