A Systems Pharmacology Approach to Rivaroxaban: Physiologically Based Modeling of Pharmacokinetics and Coagulation Dynamics

Rivaroxaban, a direct oral anticoagulant (DOAC), is a widely used drug for the prevention and treatment of thromboembolic disorders. While its fixed dosing regimen and predictable anticoagulation profile improve clinical usability, significant inter-individual variability in pharmacokinetics (PK) and pharmacodynamics (PD) exists, particularly in patients with altered physiology or comorbidities. This study established an open database of rivaroxaban PK and PD data from 14 clinical studies. The data were used to develop and validate a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of rivaroxaban that captures its absorption, distribution, metabolism, excretion, and coagulation effects. The model incorporates the effects of dose, food intake, hepatic and renal function, and allows simulation of activated Factor X (Factor Xa) inhibition, prothrombin time (PT), and activated partial thromboplastin time (aPTT). Simulations accurately reproduced observed plasma concentration-time and coagulation profiles across a range of doses, fed/fasting conditions, as well as with different degrees of cirrhosis and renal impairment. This mechanistic PBPK/PD model provides a framework for exploring variability in rivaroxaban response across diverse clinical scenarios and supports its use in personalized dosing strategies, clinical trial design, and regulatory evaluation.