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No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide

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Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated.

Methods

In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated.

Results

Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed.

Conclusions

Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide.

Clinical trial registration numbers

NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

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Notes

  1. AUC during one dosing interval (AUCτ) for digoxin.

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Acknowledgements

The authors thank the trial investigators, trial staff, and trial participants for their contributions. They would also like to express their gratitude to Dr. Helen Salter and Dr. Mark Stead for providing medical writing support, and Dr. Jenny Chien for providing scientific review and technical support.

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Authors and Affiliations

  1. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Amparo de la Peña, Xuewei Cui, Jeanne Geiser & Corina Loghin

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  1. Amparo de la Peña
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Corresponding author

Correspondence to Amparo de la Peña.

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Funding

This work was sponsored by Eli Lilly and Company.

Conflict of interest

Amparo de la Peña, Xuewei Cui, Jeanne Geiser, and Corina Loghin are employees and shareholders of Eli Lilly and Company.

Scientific meeting presentation

This work was presented in part at the annual meetings of the American Association of Clinical Endocrinologists (AACE), Nashville, TN, USA, 13–17 May 2015, and the American Society for Clinical Pharmacology and Therapeutics (ASCPT), New Orleans, LA, USA, 3–7 March 2015.

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de la Peña, A., Cui, X., Geiser, J. et al. No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide. Clin Pharmacokinet 56, 1415–1427 (2017). https://doi.org/10.1007/s40262-017-0531-7

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