Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation  

作　　者：Xiao-qin Liu Yu-fei Zhang Hong-yan Ding Ming-ming Yan Zheng Jiao Ming-kang Zhong Chun-lai Ma 

机构地区：[1]Department of Pharmacy,Huashan Hospital,Fudan University,Shanghai 200040,China [2]Department of Neurology,Huashan Hospital,Fudan University,Shanghai 200040,China [3]Department of Pharmacy,Shanghai Chest Hospital,Shanghai Jiao Tong University,Shanghai 200030,China

出　　处：《Acta Pharmacologica Sinica》2022年第10期2723-2734,共12页中国药理学报（英文版）

基　　金：This project was supported by the Shanghai“Rising Stars of Medical Talent”Youth Development Program(Youth Medical Talents-Clinical Pharmacist Program);Shanghai Key Clinical Specialty Projects-Clinical Pharmacy to Ming-kang Zhong(shslczdzk06502).

摘　　要：Rivaroxaban, a direct factor Xa inhibitor, is widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to conduct a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of rivaroxaban in Chinese patients with NVAF to assess ethnic differences and provide model-based precision dosing. A total of 256 rivaroxaban plasma concentrations and 244 prothrombin time (PT) measurements were obtained from 195 Chinese NVAF patients from a prospective clinical trial. The population PK-PD model was developed using nonlinear mixed effects modeling (NONMEM) software. The PK of rivaroxaban was adequately described using a one-compartment model with first-order adsorption and elimination. Estimated glomerular filtration rate (eGFR) was identified as a major covariate for apparent clearance. No single nucleotide polymorphism was identified as a significant covariate. PT exhibited a linear relationship with rivaroxaban concentration. Total bilirubin (TBIL) and eGFR were identified as significant covariates for baseline PT. According to the Monte Carlo simulation, 15 mg for Chinese patients with eGFR ≥50 mL/min and normal liver function yielded an exposure comparable to 20 mg for Caucasian patients. Patients with moderately impaired renal function may require a lower dose of rivaroxaban to avoid overexposure. Moreover, there was an approximate 26% increase in PT levels in patients with TBIL of 34 μmol/L and eGFR of 30 mL/min, which could increase the risk of major bleeding. The established population PK-PD model could inform individualized dosing for Chinese NVAF patients who are administered rivaroxaban.

关 键 词：RIVAROXABAN atrial fibrillation population pharmacokinetics-pharmacodynamics model-informed precision dosing Chinese 

分 类 号：R541.75[医药卫生—心血管疾病]