Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation

Jun 3, 2021Diabetes therapy : research, treatment and education of diabetes and related disorders

How Different Doses Affect the Absorption and Processing of Oral Semaglutide, a Diabetes Medication

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Abstract

In the fasting state with 120 mL of water, all subjects had measurable semaglutide exposure.

Oral semaglutide shows limited or no measurable exposure when taken with food.
Fasting conditions resulted in approximately 40% greater semaglutide exposure compared to a reference group.
Semaglutide plasma concentrations increased with longer fasting periods after dosing.
Water volume did not significantly affect semaglutide exposure in the studied conditions.
These findings inform the dosing guidelines for oral semaglutide in clinical settings.

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INTRODUCTION: Oral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide were investigated.

METHODS: Subjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose.

RESULTS: In the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration-time curve (AUC) and maximum semaglutide concentration (C) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUCand Cwere not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p < 0.001). 0-24h,semaglutide,day10max,semaglutide,day10 0-24h,semaglutide,day10max,semaglutide,day10

CONCLUSION: Administration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02172313, NCT01572753.

Key numbers

25 of 25 subjects

Fasting Group Exposure

Fasting conditions in the food-effect trial led to full exposure.

40%

40% Increase

AUC and maximum concentration were numerically higher in fasting vs. reference arms.

161

161 Participants

Participants were randomized into eight dosing groups.

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Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation

Abstract

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