Population Pharmacokinetics of Rivaroxaban in Chinese Patients with Non-Valvular Atrial Fibrillation: A Prospective Multicenter Study

作者全名："Zhang, Feilong; Chen, Xuehai; Wu, Tingting; Huang, Nianxu; Li, Li; Yuan, Dongdong; Xiang, Jing; Wang, Na; Chen, Wenjun; Zhang, Jinhua"

作者地址："[Zhang, Feilong; Chen, Xuehai] Fujian Med Univ Union Hosp, Dept Cardiol, Fuzhou, Peoples R China; [Wu, Tingting; Chen, Wenjun; Zhang, Jinhua] Fujian Med Univ Union Hosp, Dept Pharm, Fuzhou, Peoples R China; [Huang, Nianxu] Taikang Tongji Wuhan Hosp, Dept Pharm, Wuhan, Peoples R China; [Li, Li] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang, Peoples R China; [Yuan, Dongdong] Seventh Peoples Hosp Zhengzhou, Dept Pharm, Zhengzhou, Peoples R China; [Xiang, Jing; Wang, Na] Chongqing Med Univ, Dept Pharm, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Zhang, JH (通讯作者)，Fujian Med Univ Union Hosp, Dept Pharm, Fuzhou, Peoples R China."

来源：CLINICAL PHARMACOKINETICS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000771897100001

JCR分区：Q1

影响因子：4.5

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Background and Objective Rivaroxaban is a novel oral anticoagulant widely used for thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). The present study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban in Chinese patients with NVAF. Methods We performed a prospective multicenter study. The plasma concentration of rivaroxaban was directly detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and indirectly by rivaroxaban-calibrated chromogenic anti-Xa assay (STA(R)). Gene polymorphisms were detected by MassARRAY single nucleotide polymorphism genotyping technology. Nonlinear mixed-effects modeling was used to develop the PPK model for rivaroxaban in patients with NVAF, and we simulated the steady-state rivaroxaban exposures under different dosing strategies in different covariate levels. Results A total of 150 patients from five centers were recruited, including 263 plasma concentrations detected by HPLC-MS/MS, 2626 gene polymorphisms, and 131 plasma concentrations detected by anti-Xa assay. In our study, an oral one-compartment model was used to describe the pharmacokinetics of rivaroxaban in patients with NVAF. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 5.79 L/h (relative standard error [RSE] 4.4%) and 51.5 L (RSE 5.0%), respectively. Covariates in the final model included creatinine clearance, total bilirubin, rs4728709, and body weight. The simulation results showed that in the 15 mg once-daily dosing regimen, in most instances the maximum plasma concentration at steady state (C-max,C-ss) and trough plasma concentration at steady state (C-min,C-ss) were in the target range for different covariate levels. When patients were administered rivaroxaban 15 or 20 mg once daily, the C-max,C-ss and C-min,C-ss in the different bodyweight levels were also in the target range. For patients with the ABCB1 rs4728709 mutation, the C-min,C-ss in the 10, 15, and 20 mg once-daily dosing regimens were lower than the target range. The anti-Xa assay was highly linearly correlated with the HPLC-MS/MS method [y = 1.014x - 2.4648 (R-2 = 0.97)]. Conclusions Our study was the first multicenter PPK model for rivaroxaban in Chinese patients with NVAF (Alfalfa-RIVAAF-PPK). The study found that 15 mg once daily may be suitable as the principal rivaroxaban dose for Chinese patients with NVAF. For patients with the rs4728709 mutation, it may be necessary to examine insufficient anticoagulation. We found that the rivaroxaban-calibrated chromogenic anti-Xa assay and HPLC-MS/MS method were highly linearly correlated. Prospective studies with larger sample sizes and real-world studies are needed for further verification."

基金机构：　

基金资助正文：