title: Darexaban: anticoagulant effects in mice and human plasma in vitro, antithrombotic effects in thrombosis and bleeding models in mice and effects of anti-inhibitor coagulant complex and recombinant factor VIIa.
abstract: Here, we investigated the anticoagulant effects of darexaban in mice and human plasma in vitro, effects of darexaban in thrombosis and bleeding models in mice, and reversal effects of anti-inhibitor coagulant complex (ACC) and recombinant factor VIIa (rFVIIa) on anticoagulant effects of darexaban. In mice, darexaban inhibited FXa activity in plasma with an ED50 value of 24.8 mg/kg. Both darexaban and warfarin prolonged prothrombin time (PT) at 3 mg/kg and 0.3 mg/kg/day, respectively. PT and activated partial thromboplastin time (aPTT) prolonged by darexaban were dose-dependently reversed by intravenously-administered rFVIIa, significantly so at 1 mg/kg. In a pulmonary thromboembolism (PE) mouse model, both darexaban and warfarin dose-dependently reduced the mortality rate, significantly so at 10 mg/kg and 3 mg/kg/day, respectively. In a FeCl3-induced venous thrombosis (VT) mouse model, darexaban (0.3-10 mg/kg) dose-dependently decreased the thrombus protein content, significantly so at doses of 3 mg/kg or higher. In a tail-transection mouse model, darexaban had no significant effect on the amount of blood loss at doses up to 10 mg/kg, while warfarin showed a dose-dependent increase in blood loss, significantly so from 1 mg/kg/day. Darexaban and its metabolite darexaban glucuronide significantly prolonged PT and aPTT in human plasma in vitro, and while rFVIIa concentration-dependently reversed the prolonged PT in this plasma, ACC dose-dependently reversed both PT and aPTT changes prolonged by darexaban. Taken together, these results suggest that darexaban has a potential to be an oral anticoagulant with a better safety profile than warfarin, and that rFVIIa and ACC may be useful as antidotes to darexaban in cases of overdose.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc, 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. seiji.kaku@jp.astellas.com
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Mami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Minori
authors.initials: M
authors.lastname: Saitoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Funatsu
authors.forename: Toshio
authors.initials: T
authors.lastname: Uemura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology*; D001381:Azepines / Q000009:adverse effects / Q000494:pharmacology*; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000494:pharmacology; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D014859:Warfarin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D011994:Recombinant Proteins; D014859:Warfarin; C103587:recombinant FVIIa; D015942:Factor VIIa; C569750:darexaban