In silico prediction of bioequivalence of Isosorbide Mononitrate tablets with different dissolution profiles using PBPK modeling and simulation

The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches. A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by B2O simulator. The model was verified by an actual clinical study (NMPA registration number: CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results. The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance. The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.