Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Abstract Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous 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%). 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 subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

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Open Multicentre Study of the P 2T Receptor Antagonist AR-C69931MX Assessing Safety, Tolerability and Activity in Patients with Acute Coronary Syndromes

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615596 ◽

2001 ◽

Vol 85 (03) ◽

pp. 401-407 ◽

Cited By ~ 143

Author(s):

Keith Oldroyd ◽

Robert Wilcox ◽

Robert Storey ◽

Keyword(s):

Platelet Aggregation ◽

Receptor Antagonist ◽

Acute Coronary Syndromes ◽

Plasma Concentrations ◽

Antithrombotic Agent ◽

Serious Adverse Events ◽

Central Process ◽

Impedance Aggregometry ◽

Safety Parameters ◽

Coronary Syndromes

SummaryPlatelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P 2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 μg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 μg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 μmol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 ± 8.6, 94.9 ± 14.4 and 98.7 ± 2.1% and BT was 9.5 ± 8.4, 14.0 ± 9.7 and 16.0 ± 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 ± 39.2, 20.7 ± 25.9 and 40.7 ± 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of 9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.

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Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects

Xenobiotica ◽

10.1080/00498254.2019.1646440 ◽

2019 ◽

Vol 50 (4) ◽

pp. 427-434 ◽

Cited By ~ 4

Author(s):

Mike Ufer ◽

Christine Huynh ◽

Jan Jaap van Lier ◽

Eva Caroff ◽

Hartmut Fischer ◽

...

Keyword(s):

Receptor Antagonist ◽

Healthy Subjects ◽

Subcutaneous Administration ◽

P2y12 Receptor ◽

P2y12 Receptor Antagonist

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A novel P2Y12 adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models

Thrombosis and Haemostasis ◽

10.1160/th06-12-0732 ◽

2007 ◽

Vol 97 (05) ◽

pp. 847-855 ◽

Cited By ~ 23

Author(s):

Jon Vincelette ◽

Valdeci Cunha ◽

Baby Martin-McNulty ◽

Cornell Mallari ◽

Richard Fitch ◽

...

Keyword(s):

Platelet Aggregation ◽

Receptor Antagonist ◽

Thrombus Formation ◽

Therapeutic Index ◽

Bleeding Risk ◽

Adenosine Diphosphate ◽

Similar Efficacy ◽

Experimental Models ◽

P2y12 Receptor ◽

P2y12 Receptor Antagonist

SummaryIrreversible platelet inhibitors, such as aspirin and clopidogrel, have limited anti-thrombotic efficacy in the clinic due to their bleeding risk. We have developed an orally active reversible P2Y12 receptor antagonist, BX 667.The aim of this study was to determine if the reversible antagonist BX 667 had a greater therapeutic index than the irreversible P2Y12 receptor antagonist clopidogrel. Since BX 667 is rapidly converted to its active metabolite BX 048 in rats,we first injected BX 048 intravenously (iv) in a rat arterial venous (A-V) shunt model of thrombosis.BX 048 dose- and concentration-dependently attenuated thrombosis. When administered orally, BX 667 and clopidogrel had similar efficacy, but BX 667 caused less bleeding than clopidogrel. In a rat model of a platelet-rich thrombus induced by vessel injury with FeCl2, both BX 667 and clopidogrel exhibited higher levels of thrombus inhibition after oral administration compared to their potency in the A-V shunt model.Again, BX 667 caused less bleeding than clopidogrel. In a dog cyclic flow model, iv injection of either BX 667 or clopidogrel dose-dependently reduced thrombus formation with lower bleeding for BX 667 than clopidogrel. Inhibition of thrombosis was highly correlated with inhibition of ADP-induced platelet aggregation in these animal models. In dogs pre-treated with aspirin, BX 667 maintained its wider therapeutic index, measured by inhibition of platelet aggregation over bleeding, compared to the aspirin-clopidogrel combination.These data demonstrate that the reversible P2Y12 receptor antagonist, BX 667, has a wider therapeutic index than clopidogrel in experimental models of thrombosis.

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