Abstract

BackgroundPost-approval changes (PACs) in formulations requires a risk assessment of safety and efficacy for extending the product lifecycle. While BCS class I and III are candidates for biowaivers, standard bioequivalence trials are recommended for compounds with controversial classification (i.e., azithromycin). Surrogate techniques, including predictive in vitro dissolution and modeling, have shown their potential in biopharmaceutic assessment of formulations. In this paper, we aimed to assess the risk associated with PACs in azithromycin immediate-release (IR) tablets using a model-informed approach.MethodsTwo bioequivalent bio-batches (test and reference) were compared to a new test formulation. Dissolution was studied in the gastric and predictive in vitro surrogate media. This latter was tailored to azithromycin IR formulations using the reversible non-equilibrium and Mooney's models to calculate surface pH and equivalent phosphate molarities, respectively. A virtual population that matched the bioequivalence study was created using dissolution input and individual pharmacokinetic data. With these, contributions of dissolution and permeation were estimated using a series resistance model, and virtual bioequivalence was tested.ResultsThe new formulation dissolved noticeable faster in gastric media, although dissolution was comparable in surrogate media across formulations. Nonetheless, the series resistance model revealed that dissolution was much faster than transepithelial absorption, indicating absorption is rate-limited by permeability. Bioequivalence simulations supported this result.ConclusionsThe potential of integrating predictive dissolution in a model-informed PACs (MIPACs) approach was demonstrated. However, a waiver of bioequivalence studies for azithromycin may not be justified before evaluating the potential effect of excipient on azithromycin permeability.