Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects

Abstract

Background: Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin.

Methods: In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1.

Results: There were no apparent effects of oral semaglutide on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23-1.43) by oral semaglutide coadministration versus metformin alone, whereas the Cmax was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists.

Conclusions: Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Conflict of interest statement

Tine A. Bækdal, Mette Thomsen, and Thomas W. Anderson are employees of, and own stock, in Novo Nordisk A/S. Jeanett Borregaard is an employee of Novo Nordisk A/S. Cilie W. Hansen was an employee of Novo Nordisk A/S at the time of writing this manuscript.

Figures

Fig. 1

Design, dosing, and sampling for a trial 1 and b trial 2. a Lisinopril 20 mg and warfarin 25 mg (both analyzed after a single dose). b Digoxin 500 μg (single-dose analysis) and metformin 850 mg twice daily (steady-state analysis). PK denotes pharmacokinetic sampling, Dig digoxin, Lis lisinopril, Met metformin, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, War warfarin

Fig. 2

Geometric mean plasma concentration–time profiles of lisinopril, S-warfarin, digoxin, and metformin with or without coadministration of oral semaglutide or SNAC. a Lisinopril (single dose) ± oral semaglutide ± SNAC. b S-warfarin (single dose) ± oral semaglutide ± SNAC*. * Excludes the 12 subjects administered a lower dose of warfarin (administration of warfarin 5 mg instead of 25 mg) during coadministration with SNAC. c Digoxin (single dose) ± oral semaglutide ± SNAC. d Metformin (steady state) ± oral semaglutide ± SNAC. SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

Fig. 2

Geometric mean plasma concentration–time profiles of lisinopril, S-warfarin, digoxin, and metformin with or without coadministration of oral semaglutide or SNAC. a Lisinopril (single dose) ± oral semaglutide ± SNAC. b S-warfarin (single dose) ± oral semaglutide ± SNAC*. * Excludes the 12 subjects administered a lower dose of warfarin (administration of warfarin 5 mg instead of 25 mg) during coadministration with SNAC. c Digoxin (single dose) ± oral semaglutide ± SNAC. d Metformin (steady state) ± oral semaglutide ± SNAC. SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

Fig. 3

Estimated AUC and Cmax ratios (with 90% CI) for lisinopril, warfarin*, digoxin, and metformin with or without coadministration of a oral semaglutide or b SNAC. * Excludes the 12 subjects administered 5 mg warfarin instead of 25 mg during coadministration with SNAC. AUC0–12h area under the concentration–time curve from time zero to 12 h, AUC0–inf area under the concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum plasma concentration, SNAC sodium N-(8-[2-hydroxybenzoyl] amino) caprylate