First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action
| العنوان: | First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action |
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| المؤلفون: | E. Fuseau, E. Neuhart, C. Krezel, Pierre Gueret, P. L. M. van Giersbergen, S. Combe, M. Petitou |
| المصدر: | European Journal of Clinical Pharmacology. 72:1041-1050 |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, Male, Adolescent, Activated clotting time, Biotin, Oligosaccharides, 030204 cardiovascular system & hematology, Pharmacology, Models, Biological, Antithrombins, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Thrombin, Double-Blind Method, Pharmacokinetics, medicine, Humans, Pharmacology (medical), Blood coagulation test, First-in-man study, medicine.diagnostic_test, Chemistry, General Medicine, Middle Aged, 030220 oncology & carcinogenesis, Pharmacodynamics, Factor Xa, Blood Coagulation Tests, Ecarin clotting time, medicine.drug, Partial thromboplastin time |
| الوصف: | EP217609 is a parenteral antithrombotic compound combining in one molecule an indirect anti-factor Xa inhibitor, a direct thrombin active site inhibitor and a biotin moiety. The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609. In this randomised double-blind placebo-controlled study, healthy male subjects were administered intravenously single ascending doses (1, 3 or 10 mg) of EP217609 or placebo. Each treatment group consisted of 10 subjects of whom 8 received EP217609 and 2 received placebo. All doses of EP217609 were well tolerated. A total of five treatment-emergent adverse events were reported, all considered unrelated, but no bleedings or other significant adverse events occurred during this study. In both plasma and urine, there was a strong correlation between EP217609 concentrations as measured by anti-factor IIa and Xa specific bioassays indicating that the two pharmacological activities of EP217609 did not dissociate in vivo. EP217609 pharmacokinetics were dose proportional and characterised by a low clearance, a small volume of distribution and a terminal half-life of 20.4 h. The long half-life was reflected in long-lasting, dose-dependent effects on activated and ecarin clotting time, thrombin and prothrombin time, activated partial thromboplastin time, thrombin generation time and anti-factor Xa activity. Pharmacokinetic/pharmacodynamic modelling indicated that the concentration of EP217609 producing 50 % of the pharmacodynamic effect was 3400 and 2210 ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609. What is already known about this subject: • There is a limited number of neutralisable anticoagulants, particularly when rapid neutralisation is required. • Synthetic anti-Xa compounds have predictable pharmacokinetic profiles. However, problems with thrombin rebound remain because of the inability to inhibit clot-bound thrombin. What this study adds: • This manuscript provides a comprehensive investigation of the pharmacokinetics, pharmacodynamics and safety of EP217609, and the results were the basis of future clinical studies in both healthy subjects and patients. • The pharmacokinetic/pharmacodynamic modelling provided information for dose selection in such future studies. |
| تدمد: | 1432-1041 0031-6970 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f98d24b90ff1663cd7cf51659726f709 https://doi.org/10.1007/s00228-016-2077-2 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....f98d24b90ff1663cd7cf51659726f709 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14321041 00316970 |
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