Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study.Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (C max /D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban C max /D than non-carriers. Logistic regression showed that rivaroxaban C max /D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban C max /Dose and the incidence of hemorrhage events significantly.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.