title: Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban.
abstract: Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Ansell
authors.forename: Sasha H
authors.initials: SH
authors.lastname: Bakhru
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Laulicht
authors.forename: Solomon S
authors.initials: SS
authors.lastname: Steiner
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grosso
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.forename: Victor
authors.initials: V
authors.lastname: Dishy
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Lanz
authors.forename: Michele F
authors.initials: MF
authors.lastname: Mercuri
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Noveck
authors.affiliation: James C. Costin, MD., Perosphere, Inc. 20 Kenosia Ave, Danbury CT 06810, USA, Tel.: +1 203 885 1369, Fax: +1 215 619 0106, E-mail: j.costin@perosphere.com.
authors.forename: James C
authors.initials: JC
authors.lastname: Costin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001120:Arginine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects*; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009657:North Carolina; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D014914:Whole Blood Coagulation Time
chemical_list: D065427:Factor Xa Inhibitors; D010879:Piperazines; D011725:Pyridines; D013844:Thiazoles; D001120:Arginine; C552171:edoxaban; C000593571:PER977
keywords: Ciraparantag; anticoagulant; edoxaban; reversal; whole blood clotting time