Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects
Andreas B. Jordy, Muna Albayaty, Astrid Breitschaft, Thomas W. Anderson, Erik Christiansen, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A. Bækdal
Abstract
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. 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). 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). 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. NCT02845219 and NCT03010475.