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A Comparison of the Steady-State Pharmacokinetic and Pharmacodynamic Profiles of 100 and 200 U/mL Formulations of Ultra-Long-Acting Insulin Degludec

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Abstract

Background and Objective

Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which IDeg monomers are slowly and continuously absorbed to provide an ultra-long action profile. This double-blind, crossover, randomized study compared the pharmacokinetic and pharmacodynamic properties between IDeg 100 U/mL (U100) and IDeg 200 U/mL (U200) under steady-state (SS) conditions in subjects with type 1 diabetes mellitus.

Methods

Participants (n = 33 adults) underwent 8-day treatment periods with 0.4 U/kg IDeg U100 and IDeg U200 given once daily with insulin aspart at mealtimes. On day 8, a 26-h euglycaemic glucose clamp (5.5 mmol/L) was performed.

Results

The concentration–time profiles of IDeg U100 and IDeg U200 were similar, and a post-hoc analysis showed bioequivalence between these formulations, as the 90 % confidence intervals (CIs) of the U200/U100 ratios for area under the steady-state serum IDeg concentration-time curve during a dosing interval (τ; 0–24 h) (AUCτ,SS,IDeg) (0.99 [0.91–1.07]) and maximum steady-state IDeg concentration during a dosing interval (τ) (C max,SS,IDeg) (0.93 [0.84–1.02]) were within the interval 0.80–1.25. Comparable glucose infusion rates (GIR) were observed for IDeg U100 and IDeg U200 (AUCτ,SS,GIR [mg/kg]: 2,255 vs. 2,123) and the mean ratio (95 % CI) of IDeg U200/U100 for the primary endpoint (AUCτ,SS,GIR) was 0.94 [0.86–1.03]. For both formulations, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h post-dosing (U100: AUC12,SS,GIR/AUC24,SS,GIR = 48 %; U200: AUC12,SS,GIR/AUC24,SS,GIR = 46 %). Both formulations were well tolerated, and no safety events of significance were identified.

Conclusion

IDeg U100 and U200 formulations are bioequivalent and have similar pharmacodynamic profiles at SS, implying that they can be used interchangeably in clinical practice.

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Funding

This study was supported financially by Novo Nordisk A/S, Denmark, which was also responsible for the design, analysis and reporting of the study, with input from the authors. All authors were involved in the preparation and approval of the manuscript in collaboration with Novo Nordisk.

Acknowledgments

The authors thank all the subjects who participated in the study. The authors also thank Irene Vejgaard Sørensen (Novo Nordisk A/S) for assistance in preparing this paper and Mark Nelson (Watermeadow Medical, sponsored by Novo Nordisk) for assisting with the preparation of figures and tables and the submission of this article.

Conflicts of Interest

SD and KN have had no support from any organization for the submitted work; SK had support from Novo Nordisk A/S for the submitted work; SK, JKM, GK and TRP have received fees for speaking and/or consulting from Novo Nordisk A/S in the previous 3 years; CA, HT and HH are employed by and hold stock in Novo Nordisk A/S; no other relationships or activities influenced the submitted work.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Stefan Korsatko, Sigrid Deller, Gerd Koehler, Julia K. Mader, Katharina Neubauer & Thomas R. Pieber

  2. Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark

    Charlotte L. Adrian & Hanne Haahr

  3. Biostatistics, Novo Nordisk A/S, Aalborg, Denmark

    Henrik Thomsen

Authors
  1. Stefan Korsatko
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  2. Sigrid Deller
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  3. Gerd Koehler
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  4. Julia K. Mader
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  5. Katharina Neubauer
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  6. Charlotte L. Adrian
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  7. Henrik Thomsen
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  8. Hanne Haahr
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  9. Thomas R. Pieber
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Corresponding author

Correspondence to Thomas R. Pieber.

Additional information

Trial registration: ClinicalTrials.gov identifier: NCT01076634.

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Korsatko, S., Deller, S., Koehler, G. et al. A Comparison of the Steady-State Pharmacokinetic and Pharmacodynamic Profiles of 100 and 200 U/mL Formulations of Ultra-Long-Acting Insulin Degludec. Clin Drug Investig 33, 515–521 (2013). https://doi.org/10.1007/s40261-013-0096-7

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  • DOI: https://doi.org/10.1007/s40261-013-0096-7

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