Tecarfarin: A Novel Oral Anticoagulant and Characterization of it Pharmacokinetics, Tissue Distribution, and Mass Balance in Sprague‐Dawley Rats

Abstract

Tecarfarin is a novel vitamin K epoxide reductase (VKOR) inhibitor being developed for oral anticoagulation therapy for the prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and other coagulation disorders. It is metabolized to a single inactive metabolite, ATI‐5900, by human microsomal esterases, a CYP450‐independent pathway. We characterized the pharmacokinetics, tissue distribution, and mass balance of tecarfarin after IV and oral administration to Sprague‐Dawley rats. IV administration of tecarfarin was associated with a moderately rapid clearance and a low volume of distribution (Vss). Hydrolysis to ATI‐5900 was moderately fast, with Tmax of the metabolite occurring within 1 hour after that of the parent. Plasma exposure to the metabolite (AUClast) was approximately 30–50% that of the parent. Elimination half‐life (t1/2) of the parent ranged from 2.98 – 6.26 hr. Tecarfarin was well absorbed after oral administration, with oral bioavailability ranging from 80 – 90%. Following oral administration of 14C‐tecarfarin, most of the drug‐derived radioactivity was eliminated within 48 hrs, with 57% being eliminated in the feces, and 33% in the urine. In addition, tissue accumulation was low as most tissues had lower concentration of radioactivity than plasma. These results suggest that the metabolism of tecarfarin is dependent on various esterases in vivo.