Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel

Abstract

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

Keywords: GLP-1; ethinylestradiol; levonorgestrel; once weekly; semaglutide; type 2 diabetes.

© 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Study design. BW, body weight; FPG, fasting plasma glucose (at study site); HbA1c, glycosylated hemoglobin A1c; OC, oral contraceptive (dosing once-daily); PK, pharmacokinetic. Thick blue arrow, semaglutide (dosing once weekly); thin blue arrow, last dose of OC.

Figure 2

Mean concentration-time profile: 0–24 hours of levonorgestrel (n = 40) and ethinylestradiol (n = 37) during semaglutide-free and semaglutide steady-state periods. EE, ethinylestradiol; LN, levonorgestrel.

Figure 3

Mean concentration-time profile: 0–840 hours of semaglutide 1.0 mg at steady-state (n = 40). Dashed line represents the lower limit of quantification (LLOQ).

Figure 4

Mean self-measured fasting plasma glucose (FPG; measured every second day at home): self-measured FPG full analysis set (FAS; n = 43). Red dotted line represents the American Diabetes Association definition of documented symptomatic hypoglycemia. Typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration ≤3.9 mmol/L.

Figure 5

Percentage of patients with nausea by day: full analysis set (FAS; n = 43).