Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model

Bioequivalence (BE) studies support the approval and clinical use of both new and generic drug products. Narrow therapeutic index (NTI) drugs have relatively high costs and low success rates of BE evaluation clinical trials as high-risk drugs. A physiologically-based pharmacokinetic (PBPK) model can be used to evaluate the BE of two preparations. This study inputs the basic physical and chemical property parameters of warfarin sodium available at the present stage into GastroPlus™ software, and combined it with the Advanced Compartmental Absorption and Transit (ACAT™) model built into the software. The PBPK model of Chinese individuals taking 2.5 mg of warfarin sodium orally while fasted condition was developed using the disposal parameters calculated from the clinically measured PK data of the reference preparations. The model was tested using the PK data of other reference preparations and tested preparations from different domestic manufacturers. The results revealed that at least 30% of drugs are released in 30 min under a pH of 4.5 condition, and at least 80% are released in 30 min under a pH of 6.8 condition, which can be used as bioequivalent dissolution limits under fasted conditions. The risk of BE failure in the fed condition will be significantly reduced for the clinical study on the BE of warfarin sodium, which is a NTI drug if the fasted condition is bioequivalent. The results revealed that the PBPK models were successfully developed for 2.5 mg of warfarin sodium tablets in Chinese individuals. Developing a PBPK model for NTI drugs based on in vitro dissolution data in software is a promising method for BE evaluation, which can provide great help for developing new drugs and the clinical trial research of BE of generic drugs.