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. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01223-9.

Clinical Pharmacokinetics of Semaglutide: A Systematic Review

“…The median t max appeared to be similar across the treatment groups (ranged from 0.8-1.0 h). 43 This trial supports dosing of oral semaglutide in the fasting state in accordance with the prescribing information. In different post-dose fasting times groups (15,30,60, or 120 min) after overnight pre-dose fasting, semaglutide AUC 0-24h and C max increased with longer post-dose fasting periods, particularly from 15 to 30 min.…”

“…(Oral administration) Dosing conditions trial: with 50 or 120 mL water, and 15–120 min post-dose fast 10 mg (10 days) Once-daily 12 Hauge et al (2021) 42 Healthy (NA) 45 36±8 Tab. (Oral administration) Semaglutide 14 mg (5 days); Semaglutide 14 mg + five placebo tablets (5 days) Once-daily 13 van Hout et al (2023) 43 Healthy (Hispanic or Latino or Other) 156 40±12 Tab. (Oral administration) 3 mg (5 days) → 7 mg (5 days) Once-daily 14 Bækdal et al (2018a) 44 Normal hepatic function (NA) 24 49±11 Tab.…”

“…An overnight post-dose fasting trial was conducted and found that semaglutide AUC 0–24h and C max at steady state were similar for the 30 min and overnight post-dose fasting treatment groups. 43 Administration of oral semaglutide at least 30 min post-dose fasting results in clinically relevant semaglutide exposure.…”

“… 41 , 42 Drug-dosing condition interaction studies have shown that fasting for at least 30 minutes after administration of oral semaglutide with up to 120 mL water results in clinically relevant semaglutide exposure. 41 , 43 …”

“…41,42 Drug-dosing condition interaction studies have shown that fasting for at least 30 minutes after administration of oral semaglutide with up to 120 mL water results in clinically relevant semaglutide exposure. 41,43 Drug-drug interaction studies found that cagrilintide dose did not affect subcutaneous semaglutide exposure and elimination. 38 Exposure of semaglutide appeared to be slightly non-statistically significant increased when oral semaglutide was administered with omeprazole versus oral semaglutide alone.…”