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Mass Balance, Metabolism, and Excretion of Cenobamate, a New Antiepileptic Drug, After a Single Oral Administration in Healthy Male Subjects

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Abstract

Background and Objective

Cenobamate is an antiepileptic drug for the treatment of partial-onset seizures. The current study was designed to assess the mass balance and the metabolic profiling of cenobamate in humans.

Methods

Absorption, metabolism, and excretion of cenobamate were investigated in healthy male subjects after a single oral dose of 400 mg of cenobamate containing 50 µCi of [14C]-cenobamate as capsule formulation.

Results

Cenobamate was rapidly (median time to maximum plasma concentration of 1.25 h) and extensively (≥ 88% of dose) absorbed. The mean cenobamate plasma concentration–time profile revealed a multiphasic elimination profile whereas the mean plasma/blood concentration–time curve for total radioactivity did not appear to be multiphasic, suggesting that elimination mechanisms for cenobamate and its metabolites may be different. Blood/plasma ratios observed for the area under the concentration–time curve (AUC) and peak concentration (both ~ 0.60) suggest a limited penetration of cenobamate and metabolites into red blood cells (RBCs). Eight cenobamate metabolites were identified across plasma, urine, and feces. Cenobamate was the main plasma radioactive component and M1 was the only metabolite detected in plasma (> 98% and < 2% total radioactivity AUC, respectively). All detected metabolites were found in urine, with M1 as the major radioactive component (mean cumulative recovery 37.7% of dose); unchanged cenobamate accounted for 6%. Metabolites comprised ~ 88% of the dose recovered in urine, indicating extensive metabolism by the kidneys and/or metabolites formed in the liver were rapidly eliminated from the bloodstream. However, cenobamate metabolites appear to be formed slowly. Minor amounts of cenobamate (0.48%) and five metabolites (≤ 1.75% each; M1, M3, M6, M7, M11) were recovered in feces.

Conclusion

This study indicates that cenobamate is primarily eliminated in urine as metabolites. Cenobamate is the major circulating component in plasma after oral administration and has a limited penetration into RBCs.

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Acknowledgements

The authors would like to thank Staci J. McDonald, PharmD, Robert A. Earl, PhD, Ian Malloch Davis, MS, Elliot Offman, BSc Pharm, MSc, S. James Lee, PhD, Martin Brecher, MD, Palanichamy Ilankumaran, PhD and Zhaoping Yan, for study contribution. Additionally, the authors thank the staff and volunteers who participated in this study. The authors also thank Debika Chatterjea, PhD, MedVal Scientific Information Services, LLC for providing medical writing support, which was funded by SK Life Science, Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP3 Guidelines.”

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Authors and Affiliations

  1. Department of Clinical Pharmacology, SK Life Science, Inc, 461 From Road, 5th Floor, Paramus, NJ, 07652, USA

    Laurent Vernillet & Stephen A. Greene

  2. Department of Toxicology, SK Life Science, Inc, 461 From Road, 5th Floor, Paramus, NJ, 07652, USA

    Hong Wook Kim, Susan M. Melnick & Kelli Glenn

Authors
  1. Laurent Vernillet
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  2. Stephen A. Greene
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  3. Hong Wook Kim
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  4. Susan M. Melnick
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  5. Kelli Glenn
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Corresponding author

Correspondence to Laurent Vernillet.

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Funding

This study was funded by SK Life Science, Inc.

Conflict of Interest

LV, employee of SK Life Science, Inc.; SAG, employee of SK Life Science, Inc.; HWK, employee of SK Life Science, Inc.; SMM, employee of SK Life Science, Inc.; KG, employee of SK Life Science, Inc.

Data Availability Statement

The authors confirm that the data supporting the main findings of this study are available within the article [and/or] its supplementary materials. Any additional data, noted as ‘data on file’ within the text, are available from the corresponding author [LV] upon reasonable request.

Ethical Approval

This research was conducted in accordance with the clinical research guidelines established by the Medical Research Council of Canada, the Basic Principles defined in U.S. 21 CFR Part 312.20, the requirements of Directive 2001/20/EC (Europe), the principles enunciated in the Declaration of Helsinki and the ICH-harmonised tripartite guideline regarding Good Clinical Practice (GCP). The study was approved by the independent MDS Pharma Services Institutional Review Board.

Informed Consent

Informed consent was given by all subjects who participated in the study.

Previous Presentation

This data was previously presented at the 12th International Society for the Study of Xenobiotics Meeting, July 28–July 31, 2019.

Electronic supplementary material

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Supplementary file1 (PDF 424 kb)

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Vernillet, L., Greene, S.A., Kim, H.W. et al. Mass Balance, Metabolism, and Excretion of Cenobamate, a New Antiepileptic Drug, After a Single Oral Administration in Healthy Male Subjects. Eur J Drug Metab Pharmacokinet 45, 513–522 (2020). https://doi.org/10.1007/s13318-020-00615-7

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  • DOI: https://doi.org/10.1007/s13318-020-00615-7

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