Effect of tecarfarin, a novel vitamin K epoxide reductase inhibitor, on coagulation in beagle dogs.
OBJECTIVE
Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.


METHODS
Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).


RESULTS
Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K(1) treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.


CONCLUSIONS
Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.
ARYx Therapeutics, Fremont, CA 94555, USA.
A
A
Choppin
I
I
Irwin
L
L
Lach
M G
MG
McDonald
A E
AE
Rettie
L
L
Shao
C
C
Becker
M P
MP
Palme
X
X
Paliard
S
S
Bowersox
D M
DM
Dennis
P
P
Druzgala
D000284:Administration, Oral; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005167:Factor VII / Q000187:drug effects / Q000378:metabolism; D005170:Factor X / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011517:Prothrombin Time / Q000379:methods; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005466:Fluorocarbons
D000638:Amiodarone; D000925:Anticoagulants; D001189:Aryl Hydrocarbon Hydroxylases; D001565:Benzoates; D003374:Coumarins; D065729:Cytochrome P-450 CYP2C9; D005167:Factor VII; D005170:Factor X; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin; C450260:CYP2C9 protein, human; C547288:tecarfarin; D005466:Fluorocarbons