A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin

Aims To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of edoxaban, an oral direct factor Xa inhibitor, in healthy subjects switching from warfarin. Methods Seventy-two subjects were randomized to edoxaban 60mg once daily (n = 48) or matching placebo (n = 24) for 5days at 24h after the last dose of warfarin treatment (INR 2.0 to 3.0). Safety/tolerability was the primary outcome measure. Pharmacokinetics, INR, aPTT, anti-FXa, thrombin generation and other coagulation assays were assessed. Results Seventy-two subjects were randomized and 64 subjects received at least one dose of edoxaban (n = 43) or placebo (n = 21) after achieving a target INR of 2.0 to 3.0 on warfarin treatment. Edoxaban 60mg administered 24h post-warfarin appeared to be safe and well tolerated. Adverse events were similar across treatments. For bleeding-related adverse events, eight subjects tested positive for faecal occult blood, five subjects during warfarin treatment and three subjects during edoxaban treatment. The mean (SD) baseline (post-dose of warfarin) INR was 2.31 (0.193) which increased to 3.84 (0.744) over 2h during the edoxaban treatment (P < 0.0001 vs. placebo), returning to post-warfarin baseline within 12h. A similar time course of effects for the other coagulation assays was observed in accordance with the drugs' mechanisms of action. Conclusion In this study of healthy subjects, edoxaban administered 24h after the last dose of warfarin was safe and well tolerated with transient increases across the various coagulation assays above post-warfarin baseline levels.