Evaluating the bioequivalence of metronidazole tablets and analyzing the effect of in vitro dissolution on in vivo absorption based on PBPK modeling.

Metronidazole, a BCS class I drug, could be waived based on the BCS principles, thus enabling in vitro dissolution data as a surrogate of BE study. However, the impact of dissolution profiles of metronidazole tablets on the in vivo performance has never been studied systematically. So the aim of the present study was to conduct a multipronged approach of in vitro dissolution, in silico simulation, and in vivo study to evaluate the effect of dissolution performance on oral absorption of metronidazole tablets, as well as the accuracy of PBPK model to predict the oral bioavailability for BCS I drug. The results demonstrated that the PBPK models were successfully established for metronidazole immediate-release tablets. Bioequivalence comparison in dogs indicated that the test products were bioequivalent to the Reference (80%-125%, 90% CI), and even their dissolution profiles in vitro were significantly different. And the prediction of oral pharmacokinetics of the three formulations in human was also highly similar. In addition, the behavior of in vitro dissolution profiles and in vivo absorption was elucidated. These findings will contribute to understanding the potential risks during the formulation development and justifying the biowaiver for metronidazole tablets.