冠心病患者氯吡格雷群体药动学-药效学模型研究

Study on Population PK-PD Model of Clopidogrel in Patients with Coronary Heart Disease

关键词:  氯吡格雷  氯吡格雷活性代谢物  CYP2C19基因  群体药动学-药效学  体质量指数

Key words:  clopidogrel  clopidogrel active metabolite  CYP2C19 gene  population PK-PD  body mass index

摘要:

目的 建立冠心病患者氯吡格雷群体药动学-药效学模型，为尽早诊断和干预氯吡格雷抵抗提供临床依据。方法 前瞻性收集使用双联抗血小板治疗冠心病的患者101例，分别以患者体内氯吡格雷活性代谢产物(clopidogrel active metabolite，Clop-AM)浓度和血小板最大聚集率(maximum platelet aggregation rate，MAR)作为药动学和药效学指标，使用非线性混合效应模型定量考察患者性别、年龄、体质量指数(body mass index，BMI)、CYP2C19基因型、合并疾病等影响氯吡格雷抵抗的因素，建立冠心病患者氯吡格雷群体药动学-药效学模型。结果 Clop-AM表观清除率的群体典型值为2 910 L·h^-1，BMI对Clop-AM的表观清除率有影响，最终模型公式为CL=2 910×(BMI/25.09)×3.22；模型验证的平均预测误差(mean prediction error，MPE)和均方根预测误差(root mean square prediction error，RMSE)分别为药动学-药效学：MPE=0.14，RMSE=10.77；药动学：MPE=0.26，RMSE=2.91；药效学：MPE=-0.05，RMSE=17.10。结论 初步建立了冠心病患者氯吡格雷群体药动学-药效学模型，BMI较高的人群，Clop-AM清除加快，对氯吡格雷个体化用药有一定的参考价值。

Abstract:

OBJECTIVE To establish a population pharmacokinetic-pharmadynamic(PK-PD) model of clopidogrel in patients with coronary heart disease, so as to provide clinical basis for early diagnosis and intervention of clopidogrel resistance.METHODS The 101 patients with coronary heart disease were prospectively collected. Clopidogrel active metabolite (Clop-AM) concentration and maximum platelet aggregation rate(MAR) were used as pharmacokinetic and pharmacodynamic indicators. Nonlinear mixed effect model was used to quantitatively investigate the factors affecting clopidogrel resistance, such as gender, age, body mass index(BMI), CYP2C19 genotype and complications, and to establish a population PK-PD models of clopidogrel in patients with coronary heart disease.RESULTS The typical population value of the apparent clearance rate of Clop-AM was 2 910 L·h^-1. BMI had an effect on the apparent clearance of Clop-AM. The final model formula was CL=2 910×(BMI/25.09)×3.22. The mean prediction error(MPE) and the root mean square prediction error(RMSE) were PK/PD: MPE=0.14, RMSE=10.77; PK: MPE=0.26, RMSE=2.91, PD: MPE=-0.05, RMSE=17.10.CONCLUSION The population PK-PD model of clopidogrel in patients with coronary heart disease has been preliminarily established. Clop-AM clearance is accelerated in patients with high BMI. It has certain reference value for individualized administration of clopidogrel.