Impact of Administration Conditions on Absorption of the Oral GLP-1 Receptor Agonist Semaglutide (Rybelsus^®)

A Pharmaceutical Perspective

Abstract

Because the glucagon-like peptide-1 receptor agonist semaglutide is designed to be absorbed through the stomach, factors such as the gastric environment and administration method significantly influence the disintegration of the tablet and dissolution of the active ingredients. This study investigated the pharmaceutical factors contributing to inter- and intraindividual variability in the plasma concentration of semaglutide (Rybelsus^® tablets) in real-world settings by examining the formulation characteristics of tablets under various anticipated administration conditions. Furthermore, to gain insights into the effects of changes in the amount of water in the stomach over time and of the antacids to alter gastric pH, we conducted in vivo experiments in rats. Results revealed that Rybelsus^® tablets fully disintegrated within about 1 hour in tap water independent of the fluid volume. However, using a swallowing aid or acidic fluid significantly delayed tablet disintegration and salcaprozate sodium (SNAC) dissolution. Additionally, tap water is rapidly absorbed and undergoes gastric emptying, which suggests minimal water intake might not disintegrate tablets adequately. Increasing the gastric solubility of SNAC with the concomitant use of an antacid significantly increased the oral absorption of semaglutide in rats, which suggests a potential drug-drug interaction between antacids and semaglutide. Our findings identify some physiological and pharmaceutical factors that are considered to influence fluctuations in the blood concentration of semaglutide in real-world clinical practice. To our knowledge, this study is the first to provide insights from a pharmaceutics perspective into the need to adhere to the specified dosing guidelines for Rybelsus^® tablets.