Experiences and Translatability of <i>In Vitro and</i> <i>In Vivo</i> Models to Evaluate Caprate as a Permeation Enhancer

Abstract

Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various <i>in vitro</i> and <i>in vivo</i> methods have been investigated to optimize this selection. <i>In vitro</i> methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and <i>in vitro</i> methods typically have a higher throughput. This paper compares two <i>in vitro</i> methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two <i>in vivo</i> models, being <i>in situ</i> intestinal instillation to rats and <i>in vivo</i> administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the <i>in vitro</i> models in mimicking the processes occurring <i>in vivo</i>. The paper highlights the need to consider these differences when translating data generated using these <i>in vitro</i> models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.