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

Abstract

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 pharmacokinetics 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 0-24h,semaglutide,day10 ) and maximum semaglutide concentration (C max,semaglutide,day10 ) 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, AUC 0-24h,semaglutide,day10 and C max,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p \ 0.001). 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.

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“…Oral semaglutide absorption increased with longer postdose fasting periods and was comparable when administered with either 50 or 120 mL of water [57]. Complete tablet erosion was observed regardless of water volume but occurred at a slower rate with 50 mL versus 240 mL, resulting in higher semaglutide plasma exposure with lower water volumes (Fig.…”

“…In phase I studies, food and drink were found to impact the absorption of oral semaglutide, with limited or no measurable absorption reported in fed participants [57].…”

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“…After 15–35 min of oral intake, the medication reaches its maximal concentration [ 32 ]. As food interferes with drug absorption, oral semaglutide should be given while fasting [ 35 ]. Semaglutide exposure was unaffected by the amount of water used to take the drug [ 35 ].…”

“…As food interferes with drug absorption, oral semaglutide should be given while fasting [ 35 ]. Semaglutide exposure was unaffected by the amount of water used to take the drug [ 35 ]. However, the higher the semaglutide exposure, the longer the post-dose fasting time; hence, at least 30 min of post-dose fasting is recommended [ 35 ].…”

“…Semaglutide exposure was unaffected by the amount of water used to take the drug [ 35 ]. However, the higher the semaglutide exposure, the longer the post-dose fasting time; hence, at least 30 min of post-dose fasting is recommended [ 35 ]. Renal and hepatic impairment had no effect on the pharmacokinetics of oral semaglutide, indicating that individuals with renal and hepatic impairment do not require dose adjustments [ 36 , 37 ].…”