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Pharmacodynamics, Pharmacokinetics, and Safety Of European Heart Journal (2019) 0, 1–9 CLINICAL RESEARCH doi:10.1093/eurheartj/ehz807 Thrombosis and antithrombotic therapy Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehz807/5625727 by University of Newcastle user on 14 January 2020 Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes Robert F. Storey 1*, Paul A. Gurbel2, Jurrien ten Berg 3, Corine Bernaud 4, George D. Dangas5, Jean-Marie Frenoux 4, Diana A. Gorog 6,7, Abdel Hmissi 4, Vijay Kunadian8,9, Stefan K. James 10, Jean-Francois Tanguay11, Henry Tran2, Dietmar Trenk 12, Mike Ufer4, Pim Van der Harst 13, Arnoud W.J. Van’t Hof 14,15,16, and Dominick J. Angiolillo17 1Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; 2Inova Heart and Vascular Institute, Falls Church, VA, USA; 3Department of Cardiologie, St Antonius Hospital, Nieuwegein, Netherlands; 4Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland; 5Division of Cardiology, Mount Sinai Hospital, New York, NY, USA; 6University of Hertfordshire, Hertfordshire, UK; 7National Heart & Lung Institute, Imperial College, London, UK; 8Faculty of Medical Sciences, Newcastle University, Newcastle, UK; 9Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundations Trust, Newcastle Upon Tyne, UK; 10Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; 11Department of Medicine, Institut de Cardiologie de Montre´al, Universite´ de Montre´al, Montreal, Canada; 12Department of Cardiology and Angiology II, University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany; 13Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 14Department of Cardiology, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands; 15Department of Cardiology, Zuyderland Medical Centre (ZMC), Heerlen, Netherlands; 16Department of Cardiology, Isala Hospital, Zwolle, Netherlands; and 17Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA Received 12 August 2019; revised 28 September 2019; editorial decision 24 October 2019; accepted 25 October 2019 Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcuta- neous administration, in patients with chronic coronary syndromes (CCS). ................................................................................................................................................................................................... Methods In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcuta- and results neous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting >_3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked 30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). ................................................................................................................................................................................................... * Corresponding author. Tel: þ44 114 215 9554, Fax: þ44 114 271 1863, Email: r.f.storey@sheffield.ac.uk VC The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 2 R.F. Storey et al. Conclusions Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for >_8 h and reversible within 24 h. Further studies of subcutane- ous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable. Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehz807/5625727 by University of Newcastle user on 14 January 2020 ᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿᭿ Keywords Selatogrel • Platelet aggregation • Coronary artery disease • P2Y12 receptor antagonist • Pharmacodynamics • Pharmacokinetics . Introduction . Methods . The activation of platelets at sites of vascular injury is a key step in . Study population thrombus formation, mediated in part by adenosine diphosphate . Patients with CCS were identified by either (i) history of coronary artery 1 . (ADP)-induced activation of platelet P2Y12 receptors. Current . disease with coronary artery stenosis on angiography >_ 50% or (ii) previ- treatment guidelines recommend the use of dual oral antiplatelet . ously documented AMI occurring more than 3 months prior to . therapy consisting of aspirin and a platelet P2Y12 receptor antagonist . randomization. Eligible male and female patients were aged 18–85 years, inclusive, and (‘P2Y12 inhibitor’) for the management of patients with acute coron- . ary syndromes (ACS) and/or patients undergoing percutaneous cor- . females of childbearing potential were required to have a negative urine . pregnancy test both at screening and immediately before randomization. onary intervention (PCI) in order to prevent stent thrombosis and . future atherothrombotic events.2–5 In the absence of contraindica- . Patients were required to have a body weight of >_40.0 kg and have had . no changes to their current antiplatelet medication in the prior 1 month. tions, ticagrelor and prasugrel are recommended as the oral P2Y . 12 . Patients were excluded if they had conditions associated with increased inhibitors for most ACS patients in preference to clopidogrel, in view . bleeding risk or likely to impair study procedures or safety, or if they of their more potent and consistent antiplatelet effects and superior . were treated with inhibitors of organic anion-transporting polypeptide net clinical benefits.2,3 . (OATP)1B1 or OATP1B3 of which selatogrel is a substrate. Additional However, the onset of action of all oral P2Y12 inhibitors may be . exclusion criteria were ACS, PCI, any intervention for peripheral artery delayed by up to 6 h or more in the setting of acute myocardial infarc- . disease, acute ischaemic stroke, or transient ischaemic attack within tion (AMI), and the only non-oral P2Y12 inhibitor available is cangre- . 3 months prior to randomization. Detailed inclusion and exclusion crite- lor, which is administered intravenously in patients undergoing PCI . ria are presented in the Supplementary material online. when oral P2Y12 inhibitors are not indicated or not yet administered. Therefore, there is a need for a P2Y inhibitor that achieves . Study design 12 . consistently fast and effective platelet inhibition in the acute phase of . This was a prospective, multi-national, double-blind, randomized, 6,7 . placebo-controlled, parallel-group, Phase-2 study (ClinicalTrials.gov regis- amyocardialinfarction. Selatogrel (ACT-246475) is a 2-phenylpyrimidine-4-carboxamide . tration number NCT03384966) of a single s.c. administration of selatog- . rel at two dose levels in CCS patients receiving conventional background analogue that represents a novel class of reversibly-binding P2Y12 in- . antiplatelet therapy. All study procedures were performed according to hibitor, distinct from the two classes represented by ticagrelor and . protocols approved by local regulatory authorities and all patients pro- cangrelor. Selatogrel is being developed for subcutaneous (s.c.) . vided written informed consent prior to any study-mandated procedure. administration for early, pre-hospital treatment of AMI.8,9 Preclinical . Eligible patients were randomized to one of eight groups based on data from a rodent ferric chloride model suggest that selatogrel has . treatment (selatogrel or matching placebo), dose (8 or 16 mg), and s.c. in- a potentially lower risk of bleeding and Phase 1 data from healthy . jection site (thigh or abdomen) (Figure 1). The 8 and 16 mg doses of sela- subjects indicate selatogrel is well tolerated at doses up to 32 mg, . 9 . togrel were selected based on data from the single ascending dose study with a favourable pharmacodynamic (PD) and pharmacokinetic (PK) . and on modelling to achieve at least 85% inhibition
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