Establishing Prospective IVIVC for Generic Pharmaceuticals: Methodologies Assessment

Abstract

The present study was aimed to establish prospective IVIVC method for generic products using example of two different drug formulations (aprepitant capsules, immediate release and donepezil tablets, sustained release). The in vitro dissolution of these formulations was examined by using USP-II apparatus and different range of dissolution media. The dissolution profile was matched with the deconvoluted profile of drugs obtained from literature data to select biorelevant dissolution media. An IVIVC was established by using the mean fraction dissolved (FD) and mean fraction absorbed (FA) and used to simulate the plasma profile of these formulations by convolution from optimized dissolution media. The in vivo drug disposition was studied in an open label, balanced, randomized, single dose, two way crossover study in healthy subjects. Predicted PK parameters were compared with observed parameters. A positive correlation was seen between the FD and FA for both formulations with r 2 =0.989 for aprepitant and r 2 =0.995 for donepezil. The percent prediction error for both C max and AUC t were ≤15% while predicting the plasma concentration time profile for human bioequivalence studies for these formulations. Results supports use of prospective method in establishing IVIVC while predicting in vivo pharmacokinetic profile for bioequivalence studies for generic product development.