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Clinical Trial
. 2017 Nov;56(11):1391-1401.
doi: 10.1007/s40262-017-0532-6.

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

Helene Hausner  1 , Julie Derving Karsbøl  2 , Anders G Holst  2 , Jacob B Jacobsen  2 , Frank-Dietrich Wagner  3 , Georg Golor  4 , Thomas W Anderson  2
Affiliations
Clinical Trial

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

Helene Hausner et al. Clin Pharmacokinet. 2017 Nov.

Abstract

Background and objective: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects.

Methods: Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25).

Results: Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related.

Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

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Conflict of interest statement

Conflict of interest

FW and GG have no conflicts of interest to declare. HH, DK, AH, JJ and TA are full-time employees of Novo Nordisk.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by Novo Nordisk. AXON Communications provided editorial and medical writing assistance, which was funded by Novo Nordisk.

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Figures

Fig. 1
Fig. 1
Study design. Atorv atorvastatin, Dig digoxin, Met metformin, Ortho-OH ortho-hydroxylated atorvastatin metabolite, Para-OH para-hydroxylated atorvastatin metabolite, SS steady state, War warfarin. Asterisk Metformin was administered 3.5 days prior to the metformin pharmacokinetic sampling visit. Dagger Administered 48 h after the fifth dose of semaglutide 1.0 mg. Double dagger Administered 48 h after the sixth dose of semaglutide 1.0 mg. Section sign In Study 2, follow-up visit was at visit 12. The subjects received metformin and warfarin in Study 1, and atorvastatin and digoxin in Study 2
Fig. 2
Fig. 2
Mean pharmacokinetic profiles of metformin (a), S-warfarin* (b), atorvastatin (c) and digoxin (d) before and with semaglutide treatment. Reference line for the lower limit of quantification. Values below the lower limit of quantification are imputed. Asterisk R-warfarin curves are not included here but followed a similar pattern to the S-warfarin curves
Fig. 3
Fig. 3
Estimated exposure ratios for metformin, warfarin, atorvastatin and digoxin before and with semaglutide treatment. Estimated ratios, before vs. with semaglutide treatment and 90% confidence intervals are shown. AUC area under the plasma concentration–time curve, C max maximum plasma concentration (C max limits for atorvastatin and digoxin were not predefined)
Fig. 4
Fig. 4
Mean international normalised ratio (INR) profile for warfarin
See this image and copyright information in PMC

References

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