Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects

Abstract

Background: Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules.

Methods: This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects (n = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h-30 min, 4-30 min, 6 h-30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC_0-24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (C_max) (secondary endpoint).

Results: Compared with an overnight pre-dose fast (reference arm: night-30 min), shorter pre-dose fasting times in the 2 h-night, 2 h-30 min, 4 h-30 min, and 6 h-30 min treatment arms resulted in significantly lower semaglutide AUC_0-24h and C_max after the 10th dose (estimated treatment ratio ranges: 0.12-0.43 and 0.11-0.44, respectively; p < 0.0001 for all comparisons). Semaglutide AUC_0-24h and C_max after the 10th dose were similar for the 2 h-30 min and 2 h-night treatment arms.

Conclusion: This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state.

Trial registration: ClinicalTrials.gov (NCT04513704); registered August 14, 2020.

Fig. 1

Trial design (a) and overview of fasting and mealtime requirements (b). ^aOvernight fast of at least 6 h; due to the timing of the evening snack at the clinical site, the average overnight fast for treatment arm night–30 min was approximately 11 h. ^bOral semaglutide was to be dosed at 8 am (treatment arm night–30 min) or 8 pm (all other treatment arms) ± 2 h. Water intake was allowed in the specified fasting periods except from 2 h prior to dosing (all treatment arms) and until 30 min (treatment arms: 2 h–30 min, 4 h–30 min, 6 h–30 min, and night–30 min) or 2 h (treatment arm: 2 h–night) post-dosing. ^cSubjects were expected to be asleep during this time period. The post-dose meal was the first meal served for the 2 h–night treatment arm

Fig. 2

Semaglutide dosing interval profiles after the 10th dosing. Geometric means are plotted and were estimated by dosing schedule arm using a linear log-normal model accounting for censoring. Treatment arm name denotes pre-dose and post-dose fasting period; for example, 2 h–30 min indicates a pre-dose fast of 2 h and a post-dose fast of 30 min

Fig. 3

Pharmacokinetic parameters for semaglutide after the 10th dosing: AUC_{0–24h,sema,Day10} and C_{max,sema,Day10}. Boxes correspond to the 25th, 50th (median), and 75th percentiles, and solid symbols correspond to the estimated geometric means. Open circle symbols represent outliers: subjects with values for AUC_{0–24h,sema,Day10} or C_{max,sema,Day10} that are above the 95th percentile or below the 5th percentile. Whiskers correspond to the 5th and 95th percentiles. The geometric means were estimated using (a) a linear log-normal model accounting for censoring and (b) a linear normal model accounting for left-censoring. Percentiles are computed on imputed values. Treatment arm name denotes pre-dose and post-dose fasting period; for example, 2 h–30 min indicates a pre-dose fast of 2 h and a post-dose fast of 30 min. Three subjects (one each from the 6 h–30 min, 2 h–night, and night–30 min arms) were excluded from the statistical analysis: two subjects withdrew from the trial before the 10th dose and one subject had an incomplete Day 10 profile. AUC_{0–24h,sema,Day10} area under the semaglutide plasma concentration–time curve during a 24-h interval after the 10th dose of oral semaglutide, C_{max,sema,Day10} maximum observed semaglutide plasma concentration after the 10th dose of oral semaglutide

Fig. 4

Estimated treatment ratios for primary and secondary objectives. The endpoint was log-transformed and analysed in a linear normal model for censored data with dosing schedule group (five levels) and sex as fixed effects, and a residual variance parameter for each dosing group. Three subjects (one each from the 6 h–30 min, 2 h–night, and night–30 min arms) were excluded from the statistical analysis: two subjects withdrew from the trial before the 10th dose and one subject had an incomplete Day 10 profile. Treatment arm name denotes pre-dose and post-dose fasting period; for example, 2 h–30 min indicates a pre-dose fast of 2 h and a post-dose fast of 30 min. AUC_{0–24h,sema,Day10} area under the semaglutide plasma concentration–time curve during a 24-h interval after the 10th dose of oral semaglutide, CI confidence interval, C_{max,sema,Day10} maximum observed semaglutide plasma concentration after the 10th dose of oral semaglutide, ETR estimated treatment ratio