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P2X3 Receptor Antagonist Eliapixant in Phase I Clinical Trials: Safety and Inter-ethnic Comparison of Pharmacokinetics in Healthy Chinese and Japanese Participants

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Abstract

Background

Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders.

Objective

This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants.

Methods

Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed.

Results

Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (Cmax) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration–time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (Cmax,md and AUC[0–12]md) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators.

Conclusion

Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants.

Registration

ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343.

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References

  1. Bernier LP, Ase AR, Séguéla P. P2X receptor channels in chronic pain pathways. Br J Pharmacol. 2018;175(12):2219–30.

    Article  CAS  PubMed  Google Scholar 

  2. North RA. P2X3 receptors and peripheral pain mechanisms. J Physiol. 2004;554(Pt 2):301–8.

    Article  CAS  PubMed  Google Scholar 

  3. North RA. P2X receptors. Philos Trans R Soc Lond B Biol Sci. 2016;371(1700):20150427.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG, Knight GE, et al. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J Physiol. 2005;567(Pt 2):621–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Burnstock G. Purinergic signalling: therapeutic developments. Front Pharmacol. 2017;8:661.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bonvini SJ, Belvisi MG. Cough and airway disease: the role of ion channels. Pulm Pharmacol Ther. 2017;47:21–8.

    Article  CAS  PubMed  Google Scholar 

  7. Yuan M, Ding S, Meng T, Lu B, Shao S, Zhang X, et al. Effect of A-317491 delivered by glycolipid-like polymer micelles on endometriosis pain. Int J Nanomed. 2017;12:8171–83.

    Article  CAS  Google Scholar 

  8. Ryan NM, Vertigan AE, Birring SS. An update and systematic review on drug therapies for the treatment of refractory chronic cough. Expert Opin Pharmacother. 2018;19(7):687–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fabbretti E. ATP P2X3 receptors and neuronal sensitization. Front Cell Neurosci. 2013;7:236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Davenport AJ, Neagoe I, Bräuer N, Koch M, Rotgeri A, Nagel J, et al. Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers. Sci Rep. 2021;11(1):19877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Klein S, Gashaw I, Baumann S, Chang X, Hummel T, Thuß U, et al. First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: tolerability, safety and pharmacokinetics. Br J Clin Pharmacol. 2022;88(10):4552–64.

    Article  CAS  PubMed  Google Scholar 

  12. Morice A, Smith JA, McGarvey L, Birring SS, Parker SM, Turner A, et al. Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J. 2021;58(5):2004240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, et al. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020;55(3):1901615.

    Article  CAS  PubMed  Google Scholar 

  14. Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, et al. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020;8(8):775–85.

    Article  CAS  PubMed  Google Scholar 

  15. McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, et al. Efficacy and safety of gefapixant, a P2X(3) receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022;399(10328):909–23.

    Article  PubMed  Google Scholar 

  16. Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 2005;310(5753):1495–9.

    Article  CAS  PubMed  Google Scholar 

  17. Friedrich C, Francke K, Gashaw I, Scheerans C, Klein S, Fels L, et al. Safety, pharmacodynamics, and pharmacokinetics of P2X3 receptor antagonist eliapixant (BAY 1817080) in healthy subjects: double-blind randomized study. Clin Pharmacokinet. 2022;61(8):1143–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dicpinigaitis PV, Morice AH, Smith JA, Sher MR, Vaezi M, Guilleminault L, et al. Efficacy and safety of eliapixant in refractory chronic cough: the randomized, placebo-controlled phase 2b PAGANINI study. Lung. 2023;201(3):255–66.

    Article  CAS  PubMed  Google Scholar 

  19. Olafuyi O, Parekh N, Wright J, Koenig J. Inter-ethnic differences in pharmacokinetics-is there more that unites than divides? Pharmacol Res Perspect. 2021;9(6): e00890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kadian N, Raju KS, Rashid M, Malik MY, Taneja I, Wahajuddin M. Comparative assessment of bioanalytical method validation guidelines for pharmaceutical industry. J Pharm Biomed Anal. 2016;126:83–97.

    Article  CAS  PubMed  Google Scholar 

  21. Francke K, Chattopadhyay N, Klein S, Rottmann A, Krickau D, van de Wetering J, et al. Preclinical and clinical pharmacokinetics and bioavailability in healthy volunteers of a novel formulation of the selective P2X3 receptor antagonist eliapixant. Eur J Drug Metab Pharmacokinet. 2023;48(1):75–87.

    Article  CAS  PubMed  Google Scholar 

  22. Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198–205.

    Article  CAS  PubMed  Google Scholar 

  23. Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, et al. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019;54(1):1900439.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Medical writing services were provided by Kennedy Shaw, MSc, of Adelphi Communications Ltd, Macclesfield, UK and funded by Bayer AG, Berlin, Germany, in accordance with the Good Publication Practice guidelines, 2022.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, China

    Xuening Li & Hui Li

  2. Hakata Clinic, Souseikai Global Clinical Research Center, Fukuoka, Japan

    Miwa Haranaka

  3. Bayer Healthcare Co. Ltd., Clinical Pharmacology Asia, Bei**g, China

    Pei Liu & Huijun Chen

  4. Bayer AG, Clinical Pharmacology, Berlin, Germany

    Stefan Klein, Stefanie Reif, Klaus Francke & Christian Friedrich

  5. Bayer Yakuhin Ltd., Osaka, Japan

    Kazuhito Okumura

Authors
  1. Xuening Li
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  2. Miwa Haranaka
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  4. Pei Liu
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  5. Huijun Chen
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  6. Stefan Klein
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  10. Kazuhito Okumura
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Corresponding author

Correspondence to Pei Liu.

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Funding

This study was funded by Bayer AG.

Conflict of interest

P.L., H.C., S.K., S.R., K.F., and C.F. are employees of Bayer AG; K.O. works for Bayer Yakuhin Ltd.; and X.L., M.H., and H.L. have no conflicts of interest to declare.

Availability of data and material

The data underpinning this publication are made available in line with Bayer’s commitment to the principles of responsible clinical trial data sharing adhered to by the European Federation of Pharmaceutical Industries and Associations and Pharmaceutical Research and the Manufacturers of America, in relation to the scope, time point, and process of data access. Bayer commits to sharing, upon request from qualified scientific and medical researchers, patient- and study-level clinical trial data and clinical trial patient protocols for medicines and indications approved in the USA and European Union as a necessary requirement for legitimate research. This commitment applies to data on new medicines and indications that have been approved by the European Union and US regulatory agencies on or after January 1 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help to advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsor section of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.

Ethics statement

These studies were conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The protocols were reviewed and approved by each study site’s institutional review board.

Consent to participate

All participants provided written, informed consent.

Author contributions

S.R., K.F., C.F., and K.O. contributed to the design of the Japanese study. M.H. was the principal investigator of the Japanese study. P.L., H.C., S.R., K.F., and C.F. contributed to the design of the Chinese study. X.L. was the principal investigator and H.L. the sub-investigator of the Chinese study. S.K. carried out the statistical analysis in the Japanese and Chinese studies, as well as the post hoc inter-ethnic analysis. All authors interpreted the data, critically reviewed and revised the manuscript, and approved the final version for publication.

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Li, X., Haranaka, M., Li, H. et al. P2X3 Receptor Antagonist Eliapixant in Phase I Clinical Trials: Safety and Inter-ethnic Comparison of Pharmacokinetics in Healthy Chinese and Japanese Participants. Clin Pharmacokinet (2024). https://doi.org/10.1007/s40262-024-01387-y

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  • DOI: https://doi.org/10.1007/s40262-024-01387-y

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