In vitro dissolution similarity factor (f2) and in vivo bioequivalence criteria, how and when do they match? Using a BCS class II drug as a simulation example

Abstract

The present study examined the agreement between in vitro dissolution f2 similarity and in vivo bioequivalence criteria for BCS class II drugs. Dissolution test profiles were generated using the First-order model with varied dissolution parameters around the standard values of a reference profile. The in vivo curves were derived from in vitro dissolution profiles with the drug's pharmacokinetics parameters by numerical convolution method. The Cmax, Tmax, AUC0-t and AUC0-∞ obtained from in vivo test and reference concentration-time curves were compared, and the CmaxR (Cmax ratio), TmaxDif (Tmax difference), AUC0-tR (AUC0-t ratio) and AUC0-∞R (AUC0-∞ ratio) were determined. The relationships between CmaxR, AUC0-tR, AUC0-∞R, f2 and the First-order model parameters demonstrated that the Similarity Region 1 enclosed by the f2 contour line labeled 50 was completely within the Bioequivalence Region enclosed by the contour lines labeled 0.80 and 1.20 of AUC0-tR, AUC0-∞R, and CmaxR, and the Similarity Region 2 enclosed by the f2 contour line labeled 35 was nearly overlapped with the Bioequivalence Region, but did not exactly match. The results indicate that the public standard for in vitro dissolution f2 similarity criterion (f2⩾50) is probably slightly conservative and may be widened to an appropriate lower critical value.

Keywords: Bioequivalence; Dissolution; First-order; Numerical convolution; Similarity factor; Simulation.