Population pharmacokinetic study and application of ticagrelor and AR-C124910XX after percutaneous coronary intervention in Chinese patients with acute coronary syndrome.

OBJECTIVES: This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. MATERIALS AND METHODS: Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. RESULTS: The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. CONCLUSION: The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study.

BACKGROUND: ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y12 receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease. METHODS AND RESULTS: We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters. CONCLUSIONS: AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.

Diferencias en los mecanismos de acción de los nuevos antiagregantes: ¿cómo actúan? / The mechanisms of action of new antiplatelet agents. How do they work?

El tratamiento convencional con ácido acetilsalicílico y clopidogrel (una tienopiridina) ha quedado superado por el uso de nuevos inhibidores del receptor P2Y12 como prasugrel y ticagrelor. El prasugrel, al igual que toda tienopiridina, se administra oralmente e inhibe de manera irreversible el receptor, pero, pese a ser un profármaco, tiene un metabolismo más rápido y eficaz que el clopidogrel, lo que deriva en un mayor beneficio clínico. El ticagrelor (derivado nucleósido) proporciona un bloqueo reversible del receptor y no requiere bioactivación hepática, con lo que ofrece una rápida y potente inhibición plaquetaria. Además, el cangrelor y el elinogrel son dos compuestos en fase de desarrollo disponibles como formulaciones intravenosas que presentan un efecto directo, reversible y de mayor seguridad para los pacientes sometidos a cirugía coronaria. En los últimos años, de estos compuestos, y muy especialmente del ticagrelor, se han demostrado efectos beneficiosos más allá de la inhibición plaquetaria, los llamados efectos pleiotrópicos (AU)

Conventional treatment with aspirin and the thienopyridine clopidogrel has been superseded by the introduction of novel P2Y12 receptor blockers such as prasugrel and ticagrelor. Prasugrel, like all thienopyridines, is administered orally and is an irreversible inhibitor of the receptor. Despite being a prodrug, prasugrel is metabolized more rapidly and effectively than clopidogrel and consequently offers a greater clinical benefit. Ticagrelor is a nucleoside analog that reversibly blocks the receptor and does not require hepatic bioactivation, which makes it a rapid and potent platelet inhibitor. In addition, two other compounds under investigation -cangrelor and elinogrel- are available in intravenous formulations. They have a direct, reversible effect on the P2Y12 receptor and appear to have a better safety profile in patients undergoing coronary surgery. In recent years, all these compounds, and in particular ticagrelor, have been shown to have other clinical benefits in addition to platelet inhibition - their so-called pleiotropic effects (AU)

Nuevos antiagregantes plaquetarios en cardiopatía isquémica / New antiplatelet drugs in coronary artery disease

El doble tratamiento antiagregante con ácido acetilsalicílico y clopidogrel reduce considerablemente las complicaciones trombóticas de las fases aguda y crónica en la cardiopatía isquémica. Pese al buen cumplimiento terapéutico, un porcentaje no despreciable de pacientes continúa presentando episodios adversos. Por ello, nuevos compuestos farmacológicamente más favorables están ya disponibles clínicamente (como es el caso de prasugrel y ticagrelor) o en fases avanzadas de su desarrollo. La presente revisión tiene como objetivo principal la descripción de los nuevos fármacos antiagregantes, en especial prasugrel y ticagrelor (AU)

The dual antiplatelet therapy with acetylsalicylic acid and clopidogrel has been the mainstay of both acute and chronic phase coronary artery disease, reducing importantly the risk of adverse events. Despite a correct compliance, a non-negligible rate of adverse events still happens. New compounds, with improved properties, are now clinically available (such as prasugrel or ticagrelor) or under advanced development. The aim of the present review is the description of these new compounds, particularly prasugrel and ticagrelor (AU)