Physiologically Based Pharmacokinetics Modeling in Biopharmaceutics: Case Studies for Establishing the Bioequivalence Safe Space for Innovator and Generic Drugs.

For successful oral drug development, defining a bioequivalence (BE) safe space is critical for the identification of newer bioequivalent formulations or for setting of clinically relevant in vitro specifications to ensure drug product quality. By definition, the safe space delineates the dissolution profile boundaries or other drug product quality attributes, within which the drug product variants are anticipated to be bioequivalent. Defining a BE safe space with physiologically based biopharmaceutics model (PBBM) allows the establishment of mechanistic in vitro and in vivo relationships (IVIVR) to better understand absorption mechanism and critical bioavailability attributes (CBA). Detailed case studies on how to use PBBM to establish a BE safe space for both innovator and generic drugs are described. New case studies and literature examples demonstrate BE safe space applications such as how to set in vitro dissolution/particle size distribution (PSD) specifications, widen dissolution specification to supersede f2 tests, or application toward a scale-up and post-approval changes (SUPAC) biowaiver. A workflow for detailed PBBM set-up and common clinical study data requirements to establish the safe space and knowledge space are discussed. Approaches to model in vitro dissolution profiles i.e. the diffusion layer model (DLM), Takano and Johnson models or the fitted PSD and Weibull function are described with a decision tree. The conduct of parameter sensitivity analyses on kinetic dissolution parameters for safe space and virtual bioequivalence (VBE) modeling for innovator and generic drugs are shared. The necessity for biopredictive dissolution method development and challenges with PBBM development and acceptance criteria are described.