Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based Biopharmaceutics Modeling for Tacrolimus Extended-Release Capsules.

A slight variation in in vivo exposure for tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI), significantly affects the pharmacodynamics of the drug. Generic drug bioequivalence (BE) standards are stricter, necessitating accurate assessment of the rate and extent of drug release. Therefore, an in vitro dissolution method with high in vivo predictive power is crucial for developing generic drugs. In this study, physiologically based biopharmaceutics modeling (PBBM) for 5 mg tacrolimus ER capsules was developed and validated. The reference and non-BE test formulations were assessed using the Flow-Through Cell apparatus (USP IV) with biorelevant media to establish a biopredictive dissolution method. Using PBBM, virtual bioequivalence trials with virtual batches were conducted to propose a BE safe space. These criteria can identify formulations that pass the internal quality control test but are likely non-BE. This study highlights the benefits of developing biopredictive dissolution methods that are based on biorelevant dissolution. The PBBM, constructed by integrating various drug parameters, combined with the developed biopredictive dissolution methods, is a convenient approach for BE evaluation of NTI drugs and a practical tool for developing new drugs.