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, Andreas B Jordy, Muna Albayaty, Astrid Breitschaft, Thomas W Anderson, Erik Christiansen, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A Bækdal

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 (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.

Conflict of interest statement

Tine A. Bækdal, Erik Christiansen, Azadeh Houshmand-Øregaard, Easwaran Manigandan and Andreas B. Jordy are Novo Nordisk employees. Tine A. Bækdal, Thomas W. Anderson, Erik Christiansen, Azadeh Houshmand-Øregaard and Easwaran Manigandan own stocks or shares in Novo Nordisk. Thomas W. Anderson is a former employee of Novo Nordisk.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Trial design for a Trial 1 (combined OC) and b Trial 2 (furosemide/rosuvastatin). Oral semaglutide is the formulation of the active pharmaceutical ingredient semaglutide and the absorption enhancer SNAC 300 mg. F furosemide (40 mg), OC combined oral contraceptive [ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg)], PK pharmacokinetic, R rosuvastatin (20 mg), SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (300 mg), indicates semaglutide and SNAC PK assessments
Fig. 2
Fig. 2
Mean concentration–time profiles for the primary endpoints: a 0–24 h of ethinylestradiol (steady state) ± oral semaglutide ± SNAC alone (n = 25); b 0–24 h of levonorgestrel (steady state) ± oral semaglutide ± SNAC alone (n = 25); c 0–12 h of furosemide (single dose) ± oral semaglutide (n = 39; top panel) ± SNAC alone (n = 40; lower panel); and d 0–96 h of rosuvastatin (single dose) ± oral semaglutide (n = 33; top panel) ± SNAC alone (n = 40; lower panel); insets show 0-24 h interval with an expanded time scale. Oral semaglutide is the formulation of the active pharmaceutical ingredient semaglutide and the absorption enhancer SNAC 300 mg. The dashed line indicates the lower limit of quantification [2.5 pg/mL (a), 25 pg/mL (b), 5 ng/mL (c), 0.1 ng/mL (d)]. OC combined oral contraceptive, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (300 mg)
Fig. 2
Fig. 2
Mean concentration–time profiles for the primary endpoints: a 0–24 h of ethinylestradiol (steady state) ± oral semaglutide ± SNAC alone (n = 25); b 0–24 h of levonorgestrel (steady state) ± oral semaglutide ± SNAC alone (n = 25); c 0–12 h of furosemide (single dose) ± oral semaglutide (n = 39; top panel) ± SNAC alone (n = 40; lower panel); and d 0–96 h of rosuvastatin (single dose) ± oral semaglutide (n = 33; top panel) ± SNAC alone (n = 40; lower panel); insets show 0-24 h interval with an expanded time scale. Oral semaglutide is the formulation of the active pharmaceutical ingredient semaglutide and the absorption enhancer SNAC 300 mg. The dashed line indicates the lower limit of quantification [2.5 pg/mL (a), 25 pg/mL (b), 5 ng/mL (c), 0.1 ng/mL (d)]. OC combined oral contraceptive, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (300 mg)
Fig. 2
Fig. 2
Mean concentration–time profiles for the primary endpoints: a 0–24 h of ethinylestradiol (steady state) ± oral semaglutide ± SNAC alone (n = 25); b 0–24 h of levonorgestrel (steady state) ± oral semaglutide ± SNAC alone (n = 25); c 0–12 h of furosemide (single dose) ± oral semaglutide (n = 39; top panel) ± SNAC alone (n = 40; lower panel); and d 0–96 h of rosuvastatin (single dose) ± oral semaglutide (n = 33; top panel) ± SNAC alone (n = 40; lower panel); insets show 0-24 h interval with an expanded time scale. Oral semaglutide is the formulation of the active pharmaceutical ingredient semaglutide and the absorption enhancer SNAC 300 mg. The dashed line indicates the lower limit of quantification [2.5 pg/mL (a), 25 pg/mL (b), 5 ng/mL (c), 0.1 ng/mL (d)]. OC combined oral contraceptive, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (300 mg)
Fig. 3
Fig. 3
Estimated AUC and Cmax ratios (with 90% CI) for ethinylestradiol and levonorgestrel (a) and furosemide and rosuvastatin (b) with co-administration of oral semaglutide or SNAC alone. No effect is confirmed if the 90% CI is entirely within the pre-specified interval of 0.80–1.25. The ANOVA model based on the log-transformed endpoint as dependent variable and subject and period (with/without co-administration of oral semaglutide or SNAC alone) as fixed factors. Oral semaglutide is the formulation of the active pharmaceutical ingredient semaglutide and the absorption enhancer SNAC 300 mg. ANOVA analysis of variance, AUC area under the plasma concentration–time curve, AUC0-24 AUC from time zero to 24 h, AUC0-inf AUC from time zero to infinity, CI confidence interval, Cmax maximum concentration, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

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