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

Abstract

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). ResultsThe AUC values of ethinylestradiol and levonorgestrel were not affected by oral semaglutide co-administration (estimated ratios [90%

A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes

“…Many individuals with T2D are required to take multiple medications [70]. Given the mechanism of action of oral semaglutide [56], which includes delayed gastric emptying [24], a number of studies have assessed the impact of oral semaglutide/SNAC on exposure to other commonly administered oral drugs [71][72][73]. In a pharmacokinetic study, co-administration of oral semaglutide with multiple (five) placebo tablets reduced the absorption of semaglutide [74].…”

“…Other pharmacokinetic studies have shown no clinically relevant interactions -indicating that no dose adjustments are required -when oral semaglutide is administered in people receiving lisinopril, warfarin, metformin, digoxin, furosemide, rosuvastatin, ethinylestradiol/levonorgestrel, or omeprazole [24,[71][72][73]. In a study of healthy subjects, concomitant administration of oral semaglutide 2 h after intake of omeprazole -which increases gastric pH -led to a 14% increase in the area under the curve (AUC) 0-24 h,Day10 of SNAC compared with administration of oral semaglutide alone, whereas SNAC maximum concentration and time to maximum concentration (t max ) were similar with and without omeprazole.…”

Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes

“…As semaglutide cause delayed gastric emptying, it can affect the pharmacokinetics of other co-administered drugs. Numerous cross-over trials confirmed non-interference of semaglutide with the bioavailability of oral contraceptives, lisinopril, metformin, warfarin, furosemide, digoxin, atorvastatin, rosuvastatin, and omeprazole [101][102][103][104][105]. Coadministration of levothyroxine with oral semaglutide results in increased exposure of levothyroxine by 33%.…”

Recommendations for Titration and Administration of Oral Semaglutide for the Treatment of Type 2 Diabetes during Ramadan

“…An option to consider is to follow the dosing schedule for oral semaglutide when co-administered with levothyroxine and follow bedtime dosing schedules for levothyroxine in combination with increased monitoring of thyroid parameters [31][32][33]. Clinical assessments demonstrated that oral semaglutide had no significant effect on several other co-administered drugs [34]. Impact of Deviations from Preferred Oral Semaglutide Administration for Ramadan High inter-individual variability in gastrointestinal degradation of peptides, such as GLP-1RAs, might result in varying absorption rates of oral semaglutide if deviating from the optimized dosing schedule [27].…”