生理药动学模型结合体外溶出试验评价瑞格列奈片的生物等效性

Evaluation for Bioequivalence of Repaglinide Tablets by Physiologically Based Pharmacokinetics Model Combined with in Vitro Dissolution Test

关键词:  瑞格列奈片  生理药动学模型  体外溶出试验  虚拟生物等效性  GastroPlus^TM

Key words:  Repaglinide tablets  physiologically based pharmacokinetics model  dissolution in vitro test  virtual bioequivalence  GastroPlus^TM

摘要:

目的 评价国产瑞格列奈片(规格：1.0 mg)的生物等效性并探索体内外相关性更好的溶出条件。方法 分别测定4个厂家制剂在5种溶出介质中的溶出曲线，采用GastroPlus^TM软件建立瑞格列奈片的生理药动学模型，利用计算机技术模拟分析研究瑞格列奈片的体内外相关性，并基于不同厂家产品的体外溶出结果，利用Weibull函数，拟合体内释放曲线，通过群体模拟，对原研制剂和国产制剂进行虚拟生物等效性评价。结果 体外溶出试验显示在pH 1.0与水介质中，所有制剂在15 min时的平均溶出量均≥85%，溶出曲线相似；在另外3种介质中，除企业B的产品在pH 5.0介质中与原研制剂的溶出曲线相似外，其余溶出曲线的f₂值< 50。计算机技术模拟表明口服瑞格列奈片的主要吸收部位在十二指肠到空肠段，制剂在pH 5.0介质中的溶出曲线体内外相关性最好。虚拟生物等效性预测结果显示企业A和企业B的产品达峰浓度(C_max)和药时曲线下面积(AUC)的90%置信区间在80%~125%内，与原研制剂生物等效，而企业C不等效。结论 国内瑞格列奈片(规格：1.0 mg)上市产品中，除企业C产品外，其余2家企业的产品均与原研制剂具有生物等效性，为有效制剂；制剂在pH 5.0介质中的溶出曲线可作为瑞格列奈片的特征溶出曲线。

Abstract:

OBJECTIVE To evaluate the bioequivalence of Repaglinide tablets(1.0 mg) of different domestic manufactures and to explore a better dissolution method for higher in vitro and in vivo correlation.METHODS The dissolution profiles of four manufactures in five dissolution media were determined. The physiologically based pharmacokinetics model of Repaglinide tablets was established by GastroPlus^TM and the in vivo-in vitro correlation of Repaglinide tablets was studied by computer simulation. The release rate curve in vivo was fitted by Weibull function according to the dissolution results of products of different domestic manufactures in vitro. Population pharmacokinetic simulations were performed to evaluate the virtual bioequivalence of Repaglinide tablets of different domestic manufactures.RESULTS The in vitro dissolution results showed that dissolution curves of domestic Repaglinide tablets were similar to the reference in media of pH 1.0 and water as the dissolution rate in vitro of all Repaglinide tablets ≥85% in 15 min. In other 3 media, products of Corporation B were similar to the reference in media of pH 5.0, but the f₂ factors of other domestic Repaglinide tablet were < 50. Computer simulation indicated that the main absorption site of oral Repaglinide tablets was from duodenum to jejunum and the in vivo-in vitro correlation of dissolution in media of pH 5.0 was highest. The results of the virtual bioequivalence showed that the 90% confidence interval of the geometric mean of maximum concentraction(C_max) and area under concentration-time curve(AUC) were within the acceptable bioequivalence limits(80%-125%) except products of Corporation C.CONCLUSION Domestic Repaglinide tablets(1.0 mg) except products of Corporation C are available preparations as the computer simulation technology indicated that they are bioequivalent with the reference preparation. The dissolution curve in the media of pH 5.0 can be used as the characteristic dissolution curve of Repaglinide tablets.