Platelet P2Y12 receptor antagonist pharmacokinetics and pharmaco -dynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies

2010 ◽  
Vol 103 (03) ◽  
pp. 535-544 ◽  
Author(s):  
Richard Becker ◽  
Paul Gurbel
Keyword(s):  
Arterial Thrombosis ◽  
Bleeding Risk ◽  
Percutaneous Intervention ◽  
P2y12 Receptor ◽  
Clinical Events ◽  
Coagulation Proteins ◽  
Concomitant Reduction ◽  
P2y12 Receptor Antagonist ◽  
Coronary Syndromes ◽  
Stable Aggregate

SummaryThe platelet P2Y12 receptor is involved in all aspects of arterial thrombosis, including adhesion, activation, aggregation, secretion and development of a stable aggregate on which coagulation proteins can assemble and fibrin strands can mesh. Inhibition of the P2Y12 receptor has been shown convincingly to reduce cardiovascular events among patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous intervention (PCI). Current studies are exploring whether there is a threshold of platelet aggregation below which only more bleeding occurs, without a concomitant reduction in clinical events. The following review considers the potential relevance of reversible and irreversible mechanisms of P2Y12 inhibition to bleeding risk, posing the question, “Is it not only how much but how a platelet P2Y12 receptor is inhibited that determines the attributable safety profile?”

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

2007 ◽  
Vol 97 (05) ◽  
pp. 847-855 ◽  
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.

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

2019 ◽  
Vol 41 (33) ◽  
pp. 3132-3140 ◽  
Author(s):  
Robert F Storey ◽  
Paul A Gurbel ◽  
Jurrien ten Berg ◽  
Corine Bernaud ◽  
George D Dangas ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
P2y12 Receptor ◽  
Light Transmittance ◽  
Post Dose ◽  
Clinical Scenarios ◽  
P2y12 Receptor Antagonist ◽  
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.

Inhibition of ADP-induced P-selectin Expression and Platelet-Leukocyte Conjugate Formation by Clopidogrel and the P2Y12 Receptor Antagonist AR-C69931MX but not Aspirin

2002 ◽  
Vol 88 (09) ◽  
pp. 488-494 ◽  
Author(s):  
Heather Judge ◽  
Robert Wilcox ◽  
Stan Heptinstall ◽  
Robert Storey
Keyword(s):  
Heart Disease ◽  
Ischaemic Heart Disease ◽  
Inhibitory Effect ◽  
P2y12 Receptor ◽  
The Novel ◽  
Antithrombotic Agent ◽  
Therapeutic Benefits ◽  
P2y12 Receptor Antagonist ◽  
Coronary Syndromes

SummaryPlatelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.

BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase

2011 ◽  
Vol 106 (12) ◽  
pp. 1203-1214 ◽  
Author(s):  
Liang Hu ◽  
Zhichao Fan ◽  
Hongguang Du ◽  
Ran Ni ◽  
Si Zhang ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Atp Release ◽  
Bleeding Risk ◽  
P2y12 Receptor ◽  
Antithrombotic Agent ◽  
Thrombosis Model ◽  
P2y12 Antagonists ◽  
Pde Inhibition

SummaryThe addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y12 antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y12 antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y12 using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl3-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y12 antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y12 receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.

P2Y12-receptor-inhibiting antiplatelet strategies in acute coronary syndromes

2014 ◽  
Vol 34 (01) ◽  
pp. 20-28 ◽  
Author(s):  
K. Huber ◽  
T. Höchtl
Keyword(s):  
Acute Coronary Syndromes ◽  
Bleeding Risk ◽  
P2y12 Receptor ◽  
Antiplatelet Drugs ◽  
Major Adverse Cardiovascular Events ◽  
Onset Of Action ◽  
High Expectations ◽  
Coronary Syndromes ◽  
Underweight Patients ◽  
Special Patient

SummaryAntiplatelet therapy in acute coronary syndromes is essential for preventing stent thrombosis and for reducing major adverse cardiovascular events. Treatment strategy has changed over the last years by frequent use of more active agents inhibiting the ADP mediated activation of platelets instead of clopidogrel, such as prasugrel and ticagrelor. Compared to clopidogrel these modern antiplatelet drugs showed a significant reduction of efficacy endpoints as well as an acceptable safety profile in large multicenter randomized trials (TRITON TIMI 38, PLATO). Going in with higher efficacy a generally higher bleeding risk of prasugrel could be reduced by optimizing the maintenance dose in elderly and underweight patients (TRILOGY-ACS). However even prasugrel and ticagrelor have shown a delayed onset of action in special patient populations (e.g. STEMI) suggesting that the optimal ADP inhibitor has not been found yet. Results of the CHAMPION PHOENIX trial indicate that cangrelor, an intravenous agent, might fulfill these high expectations of an ideal platelet inhibitor in the first hours of an ACS in special patient cohorts.This review summarizes the results of most important clinical studies investigating the novel P2Y12 receptor inhibiting antiplatelet drugs.

Is there Sex-related Outcome Difference According to oral P2Y12 Inhibitors in Patients with Acute Coronary Syndromes? A Systematic Review and Meta-Analysis of 107,126 Patients

2019 ◽  
Vol 17 (2) ◽  
pp. 191-203
Author(s):  
Oliver Brown ◽  
Jennifer Rossington ◽  
Gill Louise Buchanan ◽  
Giuseppe Patti ◽  
Angela Hoye
Keyword(s):  
Systematic Review ◽  
Acute Coronary Syndromes ◽  
Meta Analysis ◽  
Indirect Comparison ◽  
Bleeding Risk ◽  
Cardiovascular Death ◽  
P2y12 Inhibitors ◽  
Significant Difference ◽  
Coronary Syndromes ◽  
Randomised Controlled

Background and Objectives: The majority of patients included in trials of anti-platelet therapy are male. This systematic review and meta-analysis aimed to determine whether, in addition to aspirin, P2Y12 blockade is beneficial in both women and men with acute coronary syndromes. </P><P> Methods: Electronic databases were searched and nine eligible randomised controlled studies were identified that had sex-specific clinical outcomes (n=107,126 patients). Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for a composite of cardiovascular death, myocardial infarction or stroke (MACE), and a safety endpoint of major bleeding for each sex. Indirect comparison analysis was performed to statistically compare ticagrelor against prasugrel. </P><P> Results: Compared to aspirin alone, clopidogrel reduced MACE in men (RR, 0.79; 95% CI, 0.68 to 0.92; p=0.003), but was not statistically significant in women (RR, 0.88; 95% CI, 0.75 to 1.02, p=0.08). Clopidogrel therapy significantly increased bleeding in women but not men. Compared to clopidogrel, prasugrel was beneficial in men (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02) but not statistically significant in women (RR, 0.94; 95% CI, 0.83 to 1.06; p=0.30); ticagrelor reduced MACE in both men (RR, 0.85; 95% CI, 0.77 to 0.94; p=0.001) and women (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02). Indirect comparison demonstrated no significant difference between ticagrelor and prasugrel in either sex. Compared to clopidogrel, ticagrelor and prasugrel increased bleeding risk in both women and men. </P><P> Conclusion: In summary, in comparison to monotherapy with aspirin, P2Y12 inhibitors reduce MACE in women and men. Ticagrelor was shown to be superior to clopidogrel in both sexes. Prasugrel showed a statistically significant benefit only in men; however indirect comparison did not demonstrate superiority of ticagrelor over prasugrel in women.

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