Oral administration of peptide drugs is very desirable from a patient perspective but ultimately presents significant challenges. One way to improve oral bioavailability of peptides is increasing peptide intestinal permeability through inclusion of permeation enhancers in the formulations. There are different models to evaluate permeation limitations in oral absorption ranging from in vitro cell culture assays to ex vivo intestinal tissue permeation studies to in situ rat intestinal perfusion models. All these models can be used in mechanistic studies to probe permeation as a rate-limiting factor to absorption, but especially relevant when considering peptide intestinal permeability, are the Ussing Chamber model and the in situ rat intestinal perfusion models. The models will be presented in detail including case studies of various peptide formulations.
The ex vivo Ussing Chamber permeation model is a highly useful system to screen formulation effects on peptide permeation using actual intestinal tissue in a resource sparing model compared to in vivo studies. Numerous permeation enhancing formulations of a model peptide drug, octreotide, were evaluated in the ex vivo system. Results from these studies showed octreotide permeability to be dependent on formulation compositions with apparent permeability values (Papp) to be between 0.4 X 10-6 cm/sec and 10.8 X 10-6 cm/sec. Overall the data provide a rank order of the formulations and recommendation of the formulation(s) that maximize permeability and could be considered for an in vivo study. Additionally in vivo data was collected on the lead permeation enhancing peptide formulation and was shown to provide 0.5% relative bioavailability from oral dosing of the peptide.
The in situ rat intestinal perfusion model with mesenteric cannulation can be used to simultaneously look at in vivo permeability via compound disappearance from the intestinal lumen (Peff) as well as appearance of compound/metabolites in the blood (Pblood). Use of this model allows for calculation of permeability values based on direct appearance of compound/metabolites in the mesenteric blood supply and allows for in-depth investigation of intestinal permeation and/or gut metabolism. The model is applicable to be used with peptides especially those that are unstable in the perfusion buffer/intestinal media, are known to be metabolized significantly in the intestine, or have the potential to change concentration during the experiment. Determination of the in vivo intestinal permeation of a promising oral peptide candidate as well as an investigation of the metabolism and retention of the peptide in the intestinal wall is an example of the successful use of this model. Results show the Pblood value for the peptide is 0.56 X 10-7 cm/sec. This suggests low in vivo permeation which is in alignment with the observed low preclinical bioavailability but additional studies allowed the team to gain insight into the potential permeation limitations of the peptide. Overall this presentation highlights how peptide formulation and maximizing peptide permeability are essential in the delivery of oral peptide drugs and would be a perfect showcase for the Drug Delivery and Formulation scientific session.
Becky Nofsinger is currently an Associate Principle Scientist in the Biopharmaceutics and Specialty Dosage Form group at Merck. Her main work activities relate to oral biopharmaceutics focusing on supporting oral formulation development across various clinical development stages with an expertise at the discovery/development interface, oral peptide permeation, and prodrug development. Becky obtained her PhD degree in Pharmaceutical Chemistry from the University of Kansas under Dr. Ron Borchardt. She has presented at various conferences and authored/co-authored several research and review articles.