Lack of Drug-Drug Interaction Between ATI-5923, a Novel Vitamin K Epoxide Reductase Inhibitor, and Amiodarone, in Beagle Dog

ATI-5923 is a novel oral anticoagulant that is being developed to prevent thromboembolic events associated with atrial fibrillation, prosthetic heart valves, and deep venous thrombosis. Like warfarin, it is a vitamin K epoxide reductase inhibitor. Unlike warfarin, which is metabolized by CYP2C9 and CYP3A4, ATI-5923 is metabolized by carboxylesterases. Our hypothesis is that ATI 5923 will lead to superior INR (international normalized ratio) control compared to warfarin as it will not be subject to pharmacokinetic interactions observed with many of the drugs that affect warfarin metabolism, leading to either excessive or suboptimal anticoagulation resulting in bleeding or thrombotic complications, respectively. These studies compared the efficacy of ATI-5923 to that of warfarin, when administered either intravenously (IV) or once a day orally, to produce stable anticoagulation in beagle dogs. The drug-drug interaction potential was assessed using co-administration with amiodarone, an inhibitor of CYP3A4 and CYP2C9, with either ATI-5923 or warfarin. Effects on coagulation were assessed by measuring Factor VII and X levels and prothrombin times (PT). Continuous IV infusions (5 to 9 days per dose) and oral administration of ATI 5923 and warfarin (5 to 10 days per dose) caused a dose-dependent decrease in plasma concentrations of Factor VII and Factor X, and an associated increase in PT. On a dose basis, ATI 5923 was a more potent anticoagulant than warfarin. Intravenous fresh frozen canine plasma or subcutaneous vitamin K1 treatment reversed the anticoagulant effects of orally-administered ATI-5923 in adult beagle dogs. Co-administration of amiodarone (40mg/kg for 2 days, 20mg/kg for 6 days) significantly increased the plasma levels and anticoagulation effect of warfarin (0.25mg/kg) in beagle dogs, as measured by increase PT and decrease in factor VII and X. In contrast, amiodarone had no effect on the anticoagulation parameters and plasma levels of ATI-5923 (0.3mg/kg). We conclude that ATI-5923, via a vitamin K-dependent mechanism, causes changes in key parameters of hemostasis in beagle dogs that are consistent with effective anticoagulation but without the important drug-drug interaction commonly observed with amiodarone in warfarin-treated patients.