阿托伐他汀生理药动学模型的建立

Establishment of physiologically based pharmacokinetic model of atorvastatin

目的:建立阿托伐他汀在健康人群中的生理药动学模型,预测其在人体内的组织分布及特征,为优化阿托伐他汀的治疗方案提供依据。方法:文献中获取关于阿托伐他汀理化参数及体外酶促动力学参数及数值。结合药物理化参数得到组织-血浆分配平衡系数(Kp),应用GastroPlus软件,建立阿托伐他汀的生理药动学模型,验证模型有效性,预测各器官组织中阿托伐他汀的经时变化,并运用模型预测阿托伐他汀在儿童及老年人群体内各器官组织中药物的经时变化,为个体化用药提供依据。结果:经验证,模型的有效性良好。阿托伐他汀在14个组织室均有分布,其中在血液、皮肤、肺中分布较高,Cmax分别为6.04,1.70,1.32 ng·ml-1;在脂肪和脑中分布较低,Cmax分别为0.31,0.33 ng·ml-1。儿童及老年人群体各器官组织阿托伐他汀的经时变化模型预测发现,儿童血液、皮肤、肺分布较高,Cmax分别为12.49,3.52,2.73 ng·ml-1;脑分布最低,Cmax为0.69ng·ml-1;老年血液、皮肤、肺分布较高,Cmax分别为8.97,2.53,1.96 ng·ml-1;肌肉分布最低,Cmax为0.63 ng·ml-1。结论:儿童及老年体内阿托伐他汀不同组织分布的Cmax为青年健康人群的两倍,显示年龄影响阿托伐他汀在体内的分布,儿童和老年人应用阿托伐他汀,存在较高发生不良反应的风险,应根据生理生化指标调整剂量,避免不良反应的发生。

OBJECTIVE To develop a physiologically based pharmacokinetic model of atorvastatin for predicting tissue distribution features of atorvastatin in body under healthy conditions, provide a basis for optimal treatment of atorvastatin. METHODS By retrieving drug-specific properties such as logP, protein binding, Km, Vmax from published literatures as basement of Kp, atorvastatin physiologically based pharmacokinetic model was built by GastroPlus software. Whole body distribution of atorvastatin was predicted in 14 tissue compartments. Model refinements were conducted after a comparison of simulated concentration-time profiles and pharmacokinetic parameters with observed data in healthy adults following oral administration. The model was used to predict tissue distributions of atorvastatin in children and elderly populations to investigate effects of age on drug distribution. RESULTS Simulated and observed data after oral dosing showed good agreement for all dose levels in reported normal adult population groups. Prediction results in various tissues showed： atorvastatin prototype drugs were distributed in 14 tissue compartments, it was higher in blood, skin and lung, with Cmax values of 6. 04, 1. 70 and 1.32 ng·ml-t , respectively, and lower in fat and brain, with Cmax values of 0. 31 and 0. 33 ng·ml-1 , respectively. Model predictions of atorvastatin distribution in children and elderly populations showed that, it was higher in blood, skin and lung, lowest in brain in children, with Cmax values of 12. 49, 3.52, 2. 73 and 0. 69 ng·ml-1 , respectively. It was higher in blood, skin and lung, lowest in muscle in elderly population, with Cmax values of 8. 97, 2. 53, 1.96 and 0. 63 ng.ml-1 , respectively, and Cmax values were two times as high as normal healthy people in children and elderly populations. CONCLUSION Cmax values are two times as high as normal healthy people in children and elderly populations. Age can affect drug distribution. There is a high risk of adverse reactions in children and elderly populations, so we should adjust doses according to physiological and biochemical index to avoid adverse reactions.