Comparison of antithrombotic and haemorrhagic effects of edoxaban, an oral direct factor Xa inhibitor, with warfarin and enoxaparin in rats.
BACKGROUND
Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban with clinically available anticoagulants, warfarin and enoxaparin, in rat models of thrombosis and haemorrhage.


METHODS
Rats were treated with single oral administration of edoxaban, repeated oral dosing of warfarin for 4 days and single subcutaneous administration of enoxaparin before thrombosis or haemorrhage induction. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava for 60 min. Tail template bleeding time was measured after making an incision on the tail.


RESULTS
Edoxaban at 0.3, 1 and 3mg/kg exerted dose-dependent and significant inhibition of venous thrombus formation. The 50% thrombus inhibition dose (ED(50)) was 1.9 mg/kg. At supra-therapeutic doses (10 and 20mg/kg), edoxaban significantly but moderately (less than 2-fold) prolonged bleeding time. Warfarin and enoxaparin also dose-dependently inhibited venous thrombosis and prolonged bleeding time. The ED(50) values of warfarin and enoxaparin were 0.12 mg/kg and 500 IU/kg, and the 2-fold bleeding time prolongation doses (BT2) were 0.16 mg/kg and 1700 IU/kg, respectively. The safety margin (ratio of BT2 to ED(50)) of edoxaban (>10.5) was greater than those of warfarin (1.3) and enoxaparin (3.4).


CONCLUSIONS
Edoxaban inhibited venous thrombosis comparably to warfarin and enoxaparin, and the attendant bleeding risk of edoxaban was lower than that of warfarin and enoxaparin in rats.
Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140–8710, Japan. morishima.yoshiyuki.t4@daiichisankyo.co.jp
Yoshiyuki
Y
Morishima
Yuko
Y
Honda
Chikako
C
Kamisato
Naoki
N
Tsuji
Akemi
A
Kita
Naoko
N
Edo
Toshiro
T
Shibano
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage; D017984:Enoxaparin / Q000008:administration & dosage*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006470:Hemorrhage / Q000175:diagnosis / Q000517:prevention & control*; D006490:Hemostatics / Q000008:administration & dosage; D008297:Male; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000175:diagnosis / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006490:Hemostatics; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban