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

Factor Xa (FXa) emerged as a promising target for effective anticoagulation and several FXa inhibitors are now available for the prevention of venous thromboembolism. However, in previously reported pharmacokinetic/pharmacodynamic (PK/PD) models, the complex coagulation processes and detailed information of drug action are usually unclear, which makes it difficult to predict clinical outcome at the drug discovery stage. In this study, a large-scale systems pharmacology model was developed based on several published models and clinical data. It takes into account all pathways of the coagulation network, and captures drug-specific features: plasma pharmacokinetics and drug-target binding kinetics (BKs). We aimed to predict the anticoagulation effects of FXa inhibitors in healthy subjects, and to use this model to compare the effects of compounds with different binding properties. Our model predicts the clotting time and anti-FXa effects and could thus serve as a predictive tool for the anticoagulant potential of a new compound.