基于生理药动学模型的瑞舒伐他汀口服吸收及饮食影响分析

Analysis of Oral Absorption and Dietary Effects of Rosuvastatin Based on Physiologically Based Pharmacokinetic Model

目的通过构建瑞舒伐他汀空腹状态下的生理药动学(physiologically based pharmacokinetic model,PBPK)模型,预测其餐后状态下的吸收,并探究其可能的食物效应机制,为服用他汀类药物的高脂血症患者提出合理的饮食建议,提高BCSⅢ类他汀类药物的药物吸收。方法根据文献和已有研究获得瑞舒伐他汀建模的理化参数、生物药剂学参数以及药动学参数,利用Gastro Plus^(TM)软件建立瑞舒伐他汀餐后给药的PBPK预测模型,并结合实测的血药浓度数据验证模型,判断是否可以准确预测出瑞舒伐他汀餐后的药物吸收结果,并进行参数敏感性分析。结果通过构建瑞舒伐他汀PBPK模型预测其餐后吸收,计算得到模型预测数据与实测数据的平均折叠误差和绝对平均折叠误差<2,结合模型验证的拟合相关系数表明拟合效果较好,同时参数敏感性分析提示高热量饮食、药物的油水分配系数(Log D)和渗透性对瑞舒伐他汀的吸收影响较大。结论所建立的模型能够较好地预测瑞舒伐他汀餐后状态下的吸收,基于参数敏感性分析结果,为服用BCSⅢ类他汀类药物的高脂血症患者提出合理的饮食建议,包括适当增加饮食中蛋白质的比重、减少脂肪和水溶性膳食纤维的占比等,可提高BCSⅢ类他汀类药物的肠道吸收。

OBJECTIVE To construct physiologically based pharmacokinetic model(PBPK)model of rosuvastatin in fasting state to predict its absorption in postprandial state and explore its possible food effect mechanism.At the same time,reasonable dietary suggestions were put forward for hyperlipidemia patients taking statins to improve the absorption of BCSⅢstatins.METHODS According to the literature and existing research,the physicochemical parameters,biopharmaceutical parameters and pharmacokinetic parameters of rosuvastatin modeling were obtained.The PBPK prediction model of rosuvastatin postprandial administration was established by GastroPlus^(TM) software,and the model was verified by the measured blood concentration data to determine whether the drug absorption results of rosuvastatin postprandial can be accurately predicted,and the parameter sensitivity analysis was carried out.RESULTS The PBPK model of rosuvastatin was constructed to predict its postprandial absorption.The average folding error and absolute average folding error of the model prediction data and the measured data were calculated to be less than 2,and the fitting correlation coefficient combined with model verification showed that the fitting was good.At the same time,parameter sensitivity analysis showed that high-calorie diet,drug LogD and permeability had a greater impact on the absorption of rosuvastatin.CONCLUSION The established model can better predict the absorption of rosuvastatin after meals.Based on the results of parameter sensitivity analysis,reasonable dietary recommendations are proposed for hyperlipidemia patients taking BCSⅢstatins,including appropriately increasing the proportion of protein in the diet,reducing the proportion of fat and water-soluble dietary fiber,etc.,to improve the intestinal absorption of BCSⅢstatins.