Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects

Abstract

BackgroundOral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]\xa0amino)\xa0caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.MethodsIn trial\xa01, 52 healthy subjects received lisinopril (20\xa0mg single dose) or warfarin (25\xa0mg single dose) with subsequent coadministration with SNAC alone (300\xa0mg single dose), followed by oral semaglutide 20\xa0mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500\xa0μg single dose) or metformin (850\xa0mg twice daily for 4\xa0days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial\xa01.ResultsThere were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the Cmax was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists.ConclusionsOral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.