Clinical pharmacokinetics · 2021
Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects.
Клиническое исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jordy Andreas B, Albayaty Muna, Breitschaft Astrid, Anderson Thomas W, Christiansen Erik, Houshmand-Øregaard Azadeh, Manigandan Easwaran, Bækdal Tine A
Аннотация
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 (Cmax), 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); Cmax 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 Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax 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.
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 (Cmax), 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); Cmax 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 Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax 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.