Dose Optimization of Rivaroxaban in Elderly Chinese Patients with Non-Valvular Atrial Fibrillation: Analysis of Populations Pharmacokinetics and Exposure-Response Relationships

Purpose: This study aimed to develop a population pharmacokinetic (PopPK) model in elderly Chinese patient with NVAF, characterize the pharmacokinetic variability, identify relevant covariates affecting rivaroxaban disposition, and explore the exposure-response relationship. Patients and Methods: A prospective observational study was conducted with rivaroxaban plasma samples collected and analyzed. A PopPK model was developed using the nonlinear mixed-effects modeling approach. Monte Carlo simulations were employed to explore the correlation between significant covariates and estimated drug exposure. AUC 24,ss derived from the PopPK analysis, was computed to evaluate exposure-response relationships. Results: Ninety-three elderly Chinese NVAF patients contributed 256 plasma concentrations were well described by a one-compartment PopPK model. Creatinine clearance (CrCL) and concomitant use of amiodarone were identified as significantly influencing clearance (CL). The simulation results revealed the following: (1) For patients with normal or mildly impaired renal function (CrCL ≥ 50 mL/min), both a 20 mg once-daily dosage without amiodarone and a 10 mg with amiodarone were acceptable; (2) For those with moderate to severe renal impairment (CrCL 15– 49 mL/min), a 10 mg once-daily dosage was appropriate regardless of amiodarone coadministration; (3) Although a 15 mg once-daily dosage was generally suitable from the pharmacokinetic standpoint, concomitant use of amiodarone significantly increased bleeding risk in patients (RR = 8.00, p = 0.039); (4) AUC 24,ss was significantly decreased in patients with thromboembolic events compared to those without such events (p < 0.0001), with 2840 ng·h/mL identified as the optimal cut-off value (p = 0.023). Conclusion: For elderly Chinese NVAF patients, a reduced-dose rivaroxaban regimen, specifically 10 mg once daily with amiodarone, is recommended for all patients regardless of renal function, whereas 15 mg once daily is a more optimal option for those not taking amiodarone. Based on the risk-benefit assessment, maintaining AUC 24,ss above 2840 ng·h/mL does not yield additional clinical benefit.