title: The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban.
abstract: BACKGROUND
  Edoxaban, 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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  Overall, 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.
  
  
  CONCLUSIONS
  There 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.
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States. Electronic address: kabrown@dsi.com.
authors: Karen S
authors: KS
authors: Brown
authors: Certified Consultant Pharmacists Inc., Chatham, NJ, United States.
authors: Prachi
authors: P
authors: Wickremasingha
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States.
authors: Dolly A
authors: DA
authors: Parasrampuria
authors: Celgene Corporation, Summit, NJ, United States.
authors: Daniel
authors: D
authors: Weiss
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States.
authors: Jarema
authors: J
authors: Kochan
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States.
authors: Victor
authors: V
authors: Dishy
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States.
authors: Ling
authors: L
authors: He
authors: Daiichi Sankyo Pharma Development, Edison, NJ, United States.
authors: Minggao
authors: M
authors: Shi
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000378:metabolism*; D015331:Cohort Studies; D065427:Factor Xa Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C025667:prothrombin complex concentrates; C552171:edoxaban
keywords: 3F-PCC; Coagulation; Edoxaban; Pharmacodynamics; Pharmacokinetics; Thrombin