Edoxaban Exposure-Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism.
Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (Cav) (HRCav) = 0.98 (i.e., change in the HR with every 1 ng/mL increase of Cav); the composite of recurrent DVT and nonfatal PE with HRCav = 0.99; and the composite of recurrent DVT, nonfatal PE, and all-cause mortality HRCav = 0.98, and all death using maximal edoxaban concentration (Cmax) with HR (Cmax) = 0.99. No statistical significant exposure-response relationships were found for clinically relevant bleeding or major adverse cardiovascular event. Results support the recommendation of once-daily edoxaban 60 mg, and a reduced 30 mg dose in patients with moderate renal impairment, body weight ≤60 kg, or use of P-glycoprotein inhibitors verapamil or quinidine.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
J
J
Nyberg
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
K E
KE
Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
S
S
Jönsson
Modeling and Simulation, Translational Medicine, and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
Oqp
O
Yin
Modeling and Simulation, Translational Medicine, and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
R
R
Miller
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
M O
MO
Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Ush
U
Simonsson
D000368:Aged; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D065427:Factor Xa Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D011655:Pulmonary Embolism / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D020246:Venous Thrombosis / Q000188:drug therapy*; D014859:Warfarin / Q000008:administration & dosage
D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014859:Warfarin; C552171:edoxaban