This AAPS-hosted webinar will include a review of the colocalization of permeation enhancer and therapeutic protein strategy to achieve appreciable absorption for orally administered protein therapies. This strategy hinges on the dynamic interplay of the permeation enhancer molecules and the gut wall resulting in a time dependent factor that scales the effective permeability of the protein. The expected permeation enhancement factor is expected to follow a bell-shaped trajectory, i.e. the trajectory initiates with a lag phase, followed by a rise to a peak enhancement with a potential hold, followed by a decline back to basal levels. This trajectory could be driven by luminal concentrations or bound or total enterocyte concentrations of the permeation enhancer. The model described here was added to the well-known ACAT model and parameterized using data from several experiments in preclinical species as well as in-vitro data for formulations utilizing two different permeation enhancers as well as two different proteins. These data will be reviewed along with the modeling workflow showcasing the model’s ability to describe in-vivo data across several dosing scenarios. While the model does not yet predict all of the features in the test set, it does remarkably better than previous attempts and has allowed some cross species predictions to be made. Further work remains to demonstrate successful translation to human predictions.

Panel:

• Grace Fraczkkiewicz
• Viera Lukacova
• Mridula Dogra
• Stephen Stamatis