Steady-state pharmacokinetics of oral semaglutide using semi-mechanistic pharmacokinetic modelling and population simulations.

Semaglutide (SEM) is a GLP-1 analogue, administered subcutaneously or orally. Due to its large molecular structure, it has poor oral absorption and bioavailability. The reported oral bioavailability is 0.4% to 1% in the fasting state. Sodium N-[8-{2-hydroxybenzoyl} amino] caprylate (SNAC) is used as a permeation enhancer to improve gastric permeability and oral bioavailability.This study developed a semi-mechanistic pharmacokinetic (PK) model to predict the steady-state pharmacokinetics of oral SEM, primarily using published clinical data and literature-derived parameters. The present study investigated the impact of SNAC on the gastric absorption of SEM.The semi-mechanistic PK model was developed for the intravenous (IV) and oral formulations. The oral absorption model was developed for SEM at different single doses with varying amounts of SNAC. The dose, SNAC concentration, gastrointestinal permeability, and intestinal first-pass effect impact the PK of the oral SEM. Steady-state PK studies were used to validate the single-dose oral PK model. IV, single-dose, and multiple-dose oral PK models were developed and validated.The developed semi-mechanistic model could be useful for further development of mechanistic, physiologically based pharmacokinetic (PBPK) models for formulation development, drug interactions, and the influence of pharmacokinetics in special populations.