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

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.