• Karen S Brown, Prachi Wickremasingha, Dolly A Parasrampuria, Daniel Weiss, Jarema Kochan, Victor Dishy, Ling He, and Minggao Shi.
• Daiichi Sankyo Pharma Development, Edison, NJ, United States. Electronic address: kabrown@dsi.com.
• Thromb. Res. 2015 Oct 1; 136 (4): 825-31.

BackgroundEdoxaban, a direct factor Xa inhibitor, is a once-daily, non-vitamin K antagonist oral anticoagulant. There is no established method to reverse the activity of non-vitamin K oral anticoagulants in cases of hemorrhage or urgent surgery. This study evaluated the ability of a 3-factor prothrombin complex concentrate (3F-PCC) to reverse the anticoagulatory effects of edoxaban.MethodsIn this phase 1 study, 24 healthy subjects were randomly assigned to receive a single dose of 60 or 180mg edoxaban, followed by placebo, 25IU/kg 3F-PCC, or 50IU/kg 3F-PCC. Edoxaban pharmacokinetics and pharmacodynamics, including the primary endpoint of prothrombin time (PT) and endogenous thrombin potential (ETP), were assessed. D-dimer and prothrombin fragment 1 and 2 (F1+2) were also measured.ResultsOverall, there were no apparent consistent effects of 3F-PCC on edoxaban pharmacokinetics. Administration of 3F-PCC 25 or 50IU/kg with edoxaban 60 or 180mg did not substantially accelerate the return of PT to baseline levels. However, infusion of 3F-PCC 25 and 50IU/kg did substantially accelerate return to baseline of ETP compared with placebo. D-dimer and F1+2 data did not indicate any lasting procoagulant effects of 3F-PCC infusion, although a transient increase in F1+2 was noted during and after 3F-PCC infusion. Edoxaban and 3F-PCC co-administration was well tolerated in normal healthy subjects.ConclusionsThere was no apparent reversal of PT prolongation with 3F-PCC following edoxaban infusion, but ETP was completely reversed. Co-administration of 3F-PCC was well tolerated, but a dose-dependent increase in F1+2 may reflect a procoagulant risk.Copyright © 2015. Published by Elsevier Ltd.

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