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.