Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects

BACKGROUND: The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral semaglutide may alter the pharmacokinetics of co-administered drugs via effects of semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. METHODS: Healthy, postmenopausal women (n = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects (n = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral semaglutide. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration (C(max)), with/without oral semaglutide, were within a pre-specified interval (0.80–1.25). RESULTS: The AUC values of ethinylestradiol and levonorgestrel were not affected by oral semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01–1.10] and 1.06 [0.97–1.17], respectively); C(max) was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16–1.42] and 1.41 [1.24–1.60], respectively) or C(max). SNAC alone did not affect the AUC or C(max) of ethinylestradiol, levonorgestrel or rosuvastatin; the C(max) of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). CONCLUSION: Co-administration with oral semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02845219 and NCT03010475. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s40262-020-00976-x).