瑞舒伐他汀钙片体内外一致性评价研究

In Vitro and In Vivo Consistency Study of Rosuvastatin Calcium Tablets

目的:通过体外溶出试验和体内生物等效性试验,考察瑞舒伐他汀钙仿制制剂与参比制剂的质量与疗效,同时采用GastroPlusTM进行群体药代动力学模拟,评估软件模拟预测的性能可靠性。方法:分别测定不同pH缓冲液(pH 1.0~8.0)中瑞舒伐他汀钙的溶解度;测定仿制制剂与参比制剂在pH 1.0盐酸溶液、pH 4.5醋酸盐缓冲液和pH 6.6枸橼酸盐缓冲液等3种溶出介质中的溶出曲线;采用f2因子法评价溶出曲线相似性。在28名健康成年中国志愿者中进行临床BE试验,评估两制剂的生物等效性。通过GastroPlusTM进行PK建模,在虚拟的28名健康成年中国人中进行群体药代动力学研究,将临床BE试验结果与GastroPlusTM模拟结果比较,验证虚拟生物等效性研究的可行性。结果:溶解度结果显示,瑞舒伐他汀钙属于高溶解性药物。体外溶出结果显示,仿制制剂与参比制剂在pH 1.0介质中,除批号170703的f2因子为49,其他批号的f2因子均>50,两者基本相似;在pH 4.5介质中f2因子均<50,溶出曲线不相似;在pH 6.6介质中,两者在15 min几乎完全溶出(>85%),溶出曲线相似。临床试验和软件虚拟预测BE结果均显示Cmax和AUC的几何平均比(仿制/参比)的90%CI在80%~125%的范围内,仿制制剂与参比制剂生物等效。结论:仿制制剂与参比制剂生物等效,软件模拟BE可以用于仿制药一致性评价临床前的初步研究。

Objective:To investigate the quality and efficacy of generic and reference rosuvastatin calcium tablets by in vitro dissolution test and in vivo bioequivalence(BE)test.At the same time,GastroPlusTM was used for population pharmacokinetic simulation to evaluate its reliability in prediction.Methods:The solubility of rosuvastatin calcium tablets in different pH buffers(pH 1.0-8.0)was determined.The dissolution profiles of the generic and the reference preparations in three dissolution media of pH 1.0 hydrochloric acid solution,pH 4.5 acetate buffer,pH 6.6 citrate buffer were determined,respectively.The similarity of the dissolution profiles was compared using the similarity f2 factor.Clinical BE trials were conducted in 28 healthy adult Chinese volunteers to evaluate the bioequivalence of generic and reference preparations.Population pharmacokinetic simulations were performed in a virtual 28 healthy adult Chinese and the results were compared with those of the clinical BE trials to verify the feasibility of the virtual bioequivalence study.Results:Solubility results showed that rosuvastatin calcium was a highly soluble drug.The in vitro dissolution results showed that the generic tablets were partially similar to the reference ones.The results of the virtual population simulations and the clinical BE trials showed that the 90%confidence interval(CI)of the geometric mean Cmax and AUC values were within the acceptable bioequivalence(BE)limits(80%-125%).Conclusions:The generic rosuvastatin calcium preparations are bioequivalent to the reference ones,and GastroPlusTM can be used as a powerful tool for the evaluation of generic consistency.