Development and Clinical Application of a Real-World Population Pharmacokinetic Model of Rivaroxaban in Asian Patients with Atrial Fibrillation

BACKGROUND: Rivaroxaban, a factor Xa inhibitor, is used to prevent stroke in patients of atrial fibrillation (AF). This study aimed to establish a population pharmacokinetic (PPK) model for rivaroxaban using real-world data, apply it to concentration prediction, and investigate the association between drug exposure and clinical outcomes. METHODS: Patients with AF receiving rivaroxaban were enrolled from an observational cohort (2016-2023) to measure plasma concentrations. An independent cohort was randomly selected to validate the PPK model. Clinical outcomes of interest included stroke or systemic thromboembolism, and major bleeding. RESULTS: A total of 226 patients contributed to 452 rivaroxaban concentration measurements. Rivaroxaban pharmacokinetics were adequately described using a one-compartment model with first-order elimination. The estimated apparent clearance (CL/F) and the volume of distribution (V/F) were 6.13 L/h and 45.57 L, respectively. CL/F was significantly influenced by creatinine clearance and concomitant use of cytochrome 3A4 or P-glycoprotein inhibitors, whereas V/F was associated with lean body weight. External validation demonstrated a good predictive performance at the individual level. Patients with low trough concentrations tended to have an increased risk of systemic thromboembolism, whereas those with high trough concentrations tended to have a higher risk of major bleeding. CONCLUSIONS: In an Asian population, rivaroxaban pharmacokinetics are influenced by renal function, lean body weight, and drug interactions. The developed PPK model facilitates the estimation of rivaroxaban concentrations at standardized timepoints from random samples. This provides a practical tool for standardized exposure assessment and the identification of patients at risk for adverse clinical outcomes. REGISTRATION: ClinicalTrials.gov identifier no. NCT05333666.