利伐沙班在老年非瓣膜性房颤患者体内的群体药动学

Population pharmacokinetics of rivaroxaban in elderly patients with non-valvular atrial fibrillation

目的建立利伐沙班在老年非瓣膜性房颤患者体内的群体药动学模型,探索影响药物体内行为的因素,促进患者的安全用药。方法回顾性收集某三甲医院长期服用利伐沙班的老年非瓣膜性房颤患者的血药浓度数据、人口统计学信息(年龄、性别、体质量、体质量指数)和生化指标(血浆白蛋白、血肌酐、谷丙转氨酶、谷草转氨酶)。采用非线性混合效应模型化方法,构建利伐沙班在非瓣膜性房颤患者体内的群体模型,采用拟合优度检验(GOF)考察模型的拟合优劣,Bootstrap和可视化预测检测(VPC)对模型进行验证。结果利伐沙班在老年非瓣膜性房颤患者的体内行为符合一级吸收的单室模型,性别与血清肌酐可显著影响其清除率。纳入协变量后模型的拟合优度有显著提升,Bootstrap和VPC结果表明最终模型预测准确、结果稳健。结论临床用药前应综合考虑患者的性别与血清肌酐水平,选择合理的用药方案。

Objective To determine the impact factors influencing the in vivo behaviors of rivaroxaban,and to promote rational drug use,with population pharmacokinetic model in patients with non-valvular atrial fibrillation.Methods The blood drug concentration data were retrospectively collected from elderly patients with non-valvular atrial fibrillation who took rivaroxaban.Patients’demographic information(age,sex,body mass,and body mass index),and biochemical indexes(plasma albumin,serum creatinine,glutamic-pyruvic transaminase and glutamic oxalacetic transaminase)were also collected.Nonlinear Mixed-Effects Modeling was used to construct rivaroxaban population pharmacokinetic model in elderly patients.Goodness-of-fit(GOF)plots were used to assess the base and final population pharmacokinetic model,and Bootstrap and Visual Predictive Check(VPC)were used to validate the final model.Results The in vivo behaviors of were described by one-compartment model with first-order absorption.The drug clearance was obviously affected by sex and serum creatinine.The GOF indicated that the final model was obviously improved after the incorporation of covariates(sex and serum creatinine).Bootstrap and VPC showed that the final model prediction was accurate and stable.Conclusion Before the clinical administration,it is recommended to consider the sex and serum creatinine level,and choose a reasonable medication regimen.