Xenobiotica; the fate of foreign compounds in biological systemsJun 3, 2026

How oral semaglutide is processed in the body over time using modeling and population simulations

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 4, 2026

Abstract

The oral bioavailability of semaglutide is reported to be between 0.4% and 1% in the fasting state.

Sodium N-[8-{2-hydroxybenzoyl} amino] caprylate (SNAC) is explored as a permeation enhancer to improve the gastric absorption of semaglutide.
A semi-mechanistic pharmacokinetic model was developed to predict how different doses of semaglutide and concentrations of SNAC affect absorption.
The pharmacokinetics of semaglutide are influenced by factors such as dose, SNAC concentration, gastrointestinal permeability, and intestinal first-pass effect.
The model aims to provide insights for further development of more comprehensive pharmacokinetic models relevant to drug formulation and interactions.

Simplified

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.

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How oral semaglutide is processed in the body over time using modeling and population simulations

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