Physiologically Based Biopharmaceutics Model of Apixaban for Biopharmaceutics Risk Assessment.

This study applies a Physiologically Based Biopharmaceutics Modeling (PBBM) framework to predict the bioavailability (BA) and bioequivalence (BE) of apixaban, a borderline BCS Class III/IV drug. It investigates how formulation factors, such as particle size, granulation method, and dissolution conditions, affect apixaban's in vivo behavior under fasting conditions. A PBBM approach was developed by integrating physicochemical, formulation, and drug-related parameters to simulate dissolution and absorption using a middle-out strategy for combining in silico, in vitro, and in vivo data. The Noyes-Whitney equation was used to predict dissolution influenced by particle size, granulation type, and in vitro dissolution conditions. This information was added to a compartmental absorption model of the gastrointestinal track connected to a classical compartmental model characterizing apixaban's disposition. The study validated the apixaban PBBM predictions by comparing simulated and observed pharmacokinetic profiles across several doses and immediate release formulations (solution and tablets) administered through the oral route. Results demonstrated acceptable prediction accuracy for BA and BE under various conditions. The model's simulations identified a dissolution safe space, enabling regulatory and development insights into acceptable formulation characteristics. These findings highlight the potential of PBBM in streamlining drug development, reducing clinical studies, and supporting regulatory decisions. Specifically, for apixaban, the study demonstrated that particle sizes below 120 µm ensure BE with reference formulations, while formulations with faster dissolution rates, such as smaller particle sizes, align closely with BCS biowaiver criteria. This research emphasizes PBBM as a valuable tool for optimizing drug quality and lifecycle management.