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

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) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (C) (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 and C 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 and C 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.