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.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor

“…Our model was an extended version of a previously evaluated ODE-based coagulation model (Burghaus et al, 2011). We added a vitamin K-dependent factor turn-over model and an effective warfarin action and decay module.…”

“…The model, as described previously by Burghaus et al (2011), takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, as well as the common pathways leading to fibrin generation via thrombin (Figure 1). As such, it possesses some unique features that were not included in earlier models, such as a portfolio of drug action mechanisms.…”

“…The latter scenarios have been established and tested previously (Burghaus et al, 2011). In clinical practice PT values are commonly reported as INR values to indicate the anticoagulant effect of VKAs.…”

A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

“…As a validation step for the model, data of plasma concentration vs. drug effect was used 26, 27, 28. All the datasets were obtained from above‐cited literature and digitized using GetData Graph Digitizer (version 2.22).…”

Rivaroxaban Delivery and Reversal at a Venous Flow Rate

“…Burghaus et al have recently published a computational model of rivaroxaban action that incorporates flow mediated effects 16 , however, empirical evaluations have not yet been reported. The aim of the current study is to identify the kinetics of rivaroxaban inhibition and removal from prothrombinase under venous flow conditions as a function of available rivaroxaban concentrations during a typical dosing regime.…”