Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes

Abstract

Efegatran (LY294468), a tripeptide arginal in hibitor of the catalytic site of thrombin, is being devel oped as a parenteral anticoagulant for the treatment of acute coronary syndromes. Efegatran was studied in a canine model of coronary artery thrombosis to determine its ability to prevent thrombus formation and as an ad junctive anticoagulant to thrombolysis, in phase I clinical studies, and phase II clinical studies in unstable angina. In the preclinical in vivo studies in dogs, efegatran pro duced a dose-dependent increase in clotting times and demonstrated a selectivity for thrombin time (TT) changes. The activated partial thromboplastin time (APTT)-TT ratio (that is, based on the dose to double each clotting time) determined in dogs from ex vivo blood samples was 8: 1. This observation was similar to that obtained during the phase I studies in normal volunteers where the APTT-TT ratio was 12:1. The canine and hu man clotting systems responded similarly at doses of efe gatran where comparisons could be made (0.25-1.0 mg/ kg/h). The kinetics of the anticoagulant activity of efega tran in dogs and humans were linear and nonsaturable over the dose ranges studied. Efegatran was also found to be an effective adjunctive anticoagulant during streptoki nase-induced thrombolysis in dogs, preventing reocclu sion without increasing bleeding risk. The novel an tithrombin, efegatran, has demonstrated dose-dependent and safe anticoagulation in animal and human studies. Efegatran is presently undergoing phase II clinical studies in unstable angina and acute myocardial infarction pa tients.