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

Abstract

Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30min. This trial compared the recommended dosing schedule with alternative schedules. This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3mg for 5days followed by 7mg for 5days). 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: 2h-30min, 4-30min, 6h-30min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30min). Semaglutide plasma concentration was measured regularly until 24h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC0-24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (Cmax) (secondary endpoint). Compared with an overnight pre-dose fast (reference arm: night-30min), shorter pre-dose fasting times in the 2h-night, 2h-30 min, 4h-30min, and 6h-30min treatment arms resulted in significantly lower semaglutide AUC0-24h and Cmax 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 AUC0-24h and Cmax after the 10th dose were similar for the 2h-30min and 2h-night treatment arms. This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state. ClinicalTrials.gov (NCT04513704); registered August 14, 2020.