Bioavailability/bioequivalence (BA/BE) evaluation by employing in vitro dissolution/release data and clinically relevant specification is required by the regulators. For BCS 1/BCS 3 drugs formulated as immediate release (IR) oral dosage forms, a BCS-based biowaiver may be granted based on the in vitro dissolution profiles generated across the physiologically relevant pH range. For drugs/formulations with dissolution/release limited/controlled absorption, establishing Level A in vitro – in vivo correlations (IVIVCs) can be applied and further utilized to assess whether BA/BE is recommended.

A step-wise process, conducted using the GastroPlus™ software tool, starts with PBPK modeling, followed by incorporation of in vitro dissolution/release data into the model, to develop and validate Level A IVIVCs. The PK parameters derived from the initial models are used, along with the parameters pertinent to human gastrointestinal anatomy/physiology, physicochemical, solubility and permeability data for the active pharmaceutical ingredient, and formulation-specific in vitro release/dissolution data reflective of in vivo dissolution/absorption, as the input for development of the Level A IVIVC. Applicability of the approach is illustrated using a BCS 2 drug and BCS 1/BCS 3 drugs formulated as immediate and extended release tablets, respectively. Of special note is that the GastroPlus™ PBPK modeling approach is selected following initial unsuccessful attempts to establish and validate a “conventional” Level A IVIVC for each case.

The Level A IVIVC, established using GastroPlus™ PBPK modeling and developed/validated as per regulatory recommendations, is found applicable to justify waivers for bio-studies around process/formulation changes, as well as for the assessment of additional dose strengths.