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Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment

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Abstract

Background

Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver.

Objective

The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin.

Methods

An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000 mg. Blood and urine samples were collected up to 48 h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods.

Results

Imeglimin maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with moderate hepatic impairment was 1.3-fold (90% confidence interval [CI] 1.05–1.60) and 1.5-fold (90% CI 1.19–1.82) higher than in subjects with normal hepatic function, but was not considered as clinically meaningful. Higher plasma exposure and amount of imeglimin renally excreted in moderate hepatic impaired subjects, associated with an unchanged elimination rate, suggests that this increase could be linked to a higher oral absorption and/or lower hepatic uptake in this population.

Conclusions

Imeglimin was safe and well tolerated in all subjects.

Clinical Trial Registration

EudraCT 2018-001950-83.

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References

  1. Matthaei S, Stumvoll M, Kellerer M, Haring HU. Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev. 2000;21(6):585–618.

    CAS  PubMed  Google Scholar 

  2. Meier JJ, Butler PC. Insulin secretion. Endocrinology. Philadelphia: Elsevier Saunders; 2005.

    Google Scholar 

  3. WHO. Global report on diabetes. Geneva: WHO; 2016.

    Google Scholar 

  4. Pirags V, Lebovitz H, Fouqueray P. Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. Diabetes Obes Metab. 2012;14(9):852–8.

    Article  CAS  Google Scholar 

  5. Fouqueray P, Pirags V, Inzucchi SE, Bailey CJ, Schernthaner G, Diamant M, et al. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care. 2013;36(3):565–8.

    Article  CAS  Google Scholar 

  6. Fouqueray P, Bolze S, Pirags V, Bailey CJ, Pacini G, Inzucchi SE, et al. Imeglimin, a new oral anti-hyperglycemic agent controls fasting and post-prandial glucose through an improvement in both insulin secretion and insulin sensitivity. Los Angeles: WCIR; 2015.

    Google Scholar 

  7. Dubourg J, Ueki K, Watada H, Ogawa W, Orza R, Jacolin B, et al. Imeglimin monotherapy in Japanese patients with type 2 diabetes: results from a randomised, 24-week, double-blind, placebo-controlled, phase IIb trial. European Association for the Study of Diabetes (EAS) Annual Meeting: 11–15 September 2017; Lisbon.

  8. Dubourg J. Clinical evidence to support the safety and efficacy of imeglimin in various population of patients with type 2 diabetes. European Association for the Study of Diabetes (EASD) Annual Meeting: 16–20 September 2019; Barcelona.

  9. Chevalier C, Fouqueray P, Bolze S. In vitro investigation, pharmacokinetics and disposition of imeglimin, a novel oral antidiabetic drug, in preclinical species and humans. Drug Metabolism and Disposition 2020. https://doi.org/10.1124/dmd.120.000154. https://dmd.aspetjournals.org/content/dmd/early/2020/10/01/dmd.120.000154.full.pdf. Accessed 17 Oct 2020

  10. Fouqueray P, Chevalier C, Perrimond-Dauchy S, Dubourg J, Bolze S. Pharmacokinetics of imeglimin in Caucasian and Japanese healthy subjects [(EudraCT No. 2005-001946-18; EML017008) and (EudraCT No. 2014-004679-21; PXL008-011; NCT02373150)]. 2020 [Data on file, Poxel SA, Lyon, France]

  11. Fouqueray P, Perrimond-Dauchy S, Bolze S. Imeglimin does not induce clinically relevant pharmacokinetic interactions when combined with either metformin or sitagliptin in healthy subjects. Clin Pharmacokinet. 2020;59:1261–71.

    Article  CAS  Google Scholar 

  12. Bell DS, Allbright E. The multifaceted associations of hepatobiliary disease and diabetes. Endocr Pract. 2007;13(3):300–12.

    Article  Google Scholar 

  13. US FDA. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Rockville: US FDA, Department of Health and Human Services; 2003.

    Google Scholar 

  14. European Medicines Agency. Guidelines on bioanalytical method validation. Amsterdam: European Medicines Agency; 2011.

    Google Scholar 

  15. International Conference on Harmonization. Validation of analytical procedures: text and methodology. Geneva: International Conference on Harmonization; 1995.

    Google Scholar 

  16. Tsiaoussis GI, Assimakopoulos SF, Tsamandas AC, Triantos CK, Thomopoulos KC. Intestinal barrier dysfunction in cirrhosis: current concepts in pathophysiology and clinical implications. World J Hepatol. 2015;7(17):2058–68.

    Article  Google Scholar 

  17. Pascual S, Such J, Esteban A, Zapater P, Casellas JA, Aparicio JR, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology. 2003;50(53):1482–6.

    PubMed  Google Scholar 

  18. Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, Karatza E, Triantos C, Vagianos CE, et al. Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability. Eur J Clin Invest. 2012;42(4):439–46.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Poxel SA, 259/261 Avenue Jean Jaurès, 69007, Lyon, France

    Clémence Chevalier, Julie Dubourg, Sébastien Bolze & Pascale Fouqueray

Authors
  1. Clémence Chevalier
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  2. Julie Dubourg
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  3. Sébastien Bolze
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  4. Pascale Fouqueray
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Corresponding author

Correspondence to Pascale Fouqueray.

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Funding

This study was funded by Poxel SA.

Conflict of interest

Clémence Chevalier, Julie Dubourg, Sébastien Bolze, and Pascale Fouqueray are employees of Poxel SA and may own stocks or stock options.

Author contributions

All authors designed the studies and were involved in the preparation of the manuscript, provided input, and reviewed the final draft for publication.

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Chevalier, C., Dubourg, J., Bolze, S. et al. Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment. Clin Pharmacokinet 60, 485–490 (2021). https://doi.org/10.1007/s40262-020-00948-1

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  • DOI: https://doi.org/10.1007/s40262-020-00948-1

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