Population pharmacokinetics and hemorrhagic risk analysis of rivaroxaban
in Chinese elderly patients with non-valvular atrial fibrillation
Abstract
Aim: The aim of this study was to establish a population pharmacokinetic
(PPK) model for rivaroxaban in Chinese elderly patients with NVAF to
evaluate precision dosing regimens and analyze hemorrhagic risk after
rivaroxaban treatment. Method: A population pharmacokinetic model was
developed using the nonlinear mixed-effects model (NONMEM). The plasma
concentration of rivaroxaban was detected by UPLC-MS/MS method and the
gene polymorphisms were detected by Sanger dideoxy DNA sequencing
method. A Monte Carlo simulation was performed to evaluate various
dosing schemes and different levels of covariates for the target range
of therapeutic drug monitoring concentrations (Cmax,ss, Cmin,ss).
Exposure of rivaroxaban was simulated and assessed in hemorrhagic risk
evaluation. Results: Model-building dataset including 360 plasma
concentrations from 180 Chinese elderly patients (median age 81year). A
one-compartment population PK model with estimated glomerular filtration
rate (eGFR), total bilirubin (TBIL) and ABCB1 rs1045642 as major
covariates for apparent clearance were developed. The average
probability of target attainment (PTA) of optimal dosing regimens with
different covariates levels for targeted Cmax,ss and Cmin,ss were
29.35%-31.30% and 64.91%-65.80%, respectively. 10 mg of rivaroxaban
in Chinese elderly patients with normal renal and liver function was
appropriate. AUC24,ss was statistically significant associated with the
increased risk of the bleeding events (OR 1.0006; 95%CL 1.0003-1.001;
p<0.0001). Conclusion: Lower dose is recommended for older
patients with renal impairment to avoid overexposure and bleeding
events. The population pharmacokinetic model could inform individualized
dosing for Chinese older NVAF patients with rivaroxaban anticoagulation
therapy.