Rivaroxaban: a new oral factor Xa inhibitor.
Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC(50)], >20 micromol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K(i)], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k(on)], 1.7x10(7) mol/L(-1) s(-1)) and reversibly (kinetic dissociation rate constant [k(off)], 5x10(-3) s(-1)). By inhibiting prothrombinase complex-bound (IC(50), 2.1 nmol/L) and clot-associated factor Xa (IC(50), 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.
Perzborn
Elisabeth
E
Cardiovascular Pharmacology, Pharma R&D Discovery Research, Bayer Schering Pharma AG, Aprather Weg 18a, D-42096 Wuppertal, Germany. elisabeth.perzborn@bayerhealthcare.com
Roehrig
Susanne
S
Straub
Alexander
A
Kubitza
Dagmar
D
Mueck
Wolfgang
W
Laux
Volker
V
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000517:prevention & control
D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban