title: Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation.
abstract: Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration-effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies.
authors.affiliation: Bayer Schering Pharma AG, Wuppertal, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Burghaus
authors.forename: Katrin
authors.initials: K
authors.lastname: Coboeken
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaub
authors.forename: Lars
authors.initials: L
authors.lastname: Kuepfer
authors.forename: Anke
authors.initials: A
authors.lastname: Sensse
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Siegmund
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weiss
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueck
authors.forename: Joerg
authors.initials: J
authors.lastname: Lippert
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001775:Blood Circulation / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects*; D003198:Computer Simulation; D017984:Enoxaparin / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000009:adverse effects* / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D011422:Propionates / Q000494:pharmacology; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects* / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D016896:Treatment Outcome; D014859:Warfarin / Q000494:pharmacology
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D017984:Enoxaparin; D009025:Morpholines; D009281:Naphthalenes; D011422:Propionates; D013876:Thiophenes; C426686:ximelagatran; D014859:Warfarin; D000069552:Rivaroxaban