Oral absorption of semaglutide: pharmacokinetic modeling and molecular dynamics simulations.

Semaglutide is a GLP-1 receptor agonist that is formulated for oral administration as Rybelsus®. Structurally, semaglutide is a lipid-modified alpha-helical peptide and its absorption, which occurs mainly from the stomach, may be dependent on its conformational properties. Therefore, it is important to include three-dimensional structural parameters that reflect conformation in a pharmacokinetic model of semaglutide. We used pharmacokinetic modeling to simulate the absorption of semaglutide and identify molecular and physiological parameters that may govern this process. A molecular radius of 5.8 Å and a gastric pore radius of 10.25 Å were required to reproduce the observed stomach absorption and plasma concentration vs. time profile of oral semaglutide at a dose of 10 mg. To determine if this molecular radius can be achieved conformationally, molecular dynamics simulations were performed. These simulations showed that the linker-lipid chain of semaglutide wraps around the peptide alpha-helix and produces a helical structure with an average molecular radius (including the peptide, linker and lipid) that falls in the same range as that required in the pharmacokinetic model. Therefore, this linker-lipid wrapping may be necessary for semaglutide to be absorbed into the systemic circulation. This work shows the potential for using molecular modeling in parameterization of pharmacokinetic models for molecules in which conformational variability may influence the pharmacokinetics. Graphical abstract: Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00393-7.