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Pharmacokinetics, Safety, and Tolerability of Intravenous Felbinac Trometamol in Healthy Chinese Volunteers: A First-in-Human Single- and Multiple-Dose Escalation Phase I Study with a Randomized, Double-Blind, Placebo-Controlled Design

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Abstract

Background

Felbinac trometamol, an anti-inflammatory and analgesic drug, has been used to treat immediate postoperative pain.

Objective

The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single or multiple intravenous infusions of felbinac trometamol in healthy Chinese volunteers.

Methods

A total of 56 healthy subjects were enrolled in a single-ascending dose study (11.78–377.00 mg), meanwhile 36 subjects were enrolled in a multiple-ascending dose study (47.13–188.50 mg). Safety endpoints included treatment-emergent adverse events, vital signs, electrocardiograms, and laboratory parameters. Pharmacokinetic endpoints included exposure of subjects to felblinac and metabolites of the drug in plasma, urine, and feces.

Results

Felblinac time to maximum plasma concentration was obtained at 0.5 h, corresponding to the end of the infusion. Maximum plasma concentration and area under the curve increased in a dose-dependent manner for felblinac and its metabolite, showing linear pharmacokinetic characteristics at single and multiple doses. After intravenous infusions of multiple doses three times (30 min each time) per day, the accumulation ratio of felblinac and its metabolite based on the area under the curve had a range of 1.34–1.45 and 1.60–1.87, respectively, across cohorts. After administration of the fourth dose, the plasma concentration of both felblinac and its metabolites was maintained at a steady state. Felbinac trometamol was well tolerated. Neither treatment-emergent adverse event frequency nor severity increased with increasing felbinac trometamol dose.

Conclusions

Felbinac trometamol was well tolerated in our study. Based on the dose range in this study, 94.25 mg is the recommended target dose for a phase II study.

Clinical Trial Registration

CTR20170496 and CTR20180896. The dates of registration are 2017-06-19 and 2018-07-02 (https://www.chinadrugtrials.org.cn/).

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References

  1. Ingrasciotta Y, Sultana J, Giorgianni F, Menditto E, Scuteri A, Tari M, et al. Analgesic drug use in elderly persons: a population-based study in Southern Italy. PLoS ONE. 2019;14(9):e0222836. https://doi.org/10.1371/journal.pone.0222836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schechter BA. Use of topical bromfenac for treating ocular pain and inflammation beyond cataract surgery: a review of published studies. Clin Ophthalmol. 2019;13:1439–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55(2):108–33.

    Article  PubMed  Google Scholar 

  4. Guo CG, Leung WK. Potential strategies in the prevention of nonsteroidal anti-inflammatory drugs-associated adverse effects in the lower gastrointestinal tract. Gut Liver. 2020;14(2):179–89. https://doi.org/10.5009/gnl19201.

    Article  PubMed  Google Scholar 

  5. Baraf HS, Fuentealba C, Greenwald M, et al. Gastrointestinal side effects of etoricoxib in patients with osteoarthritis: results of the etoricoxib versus diclofenac sodium gastrointestinal tolerability and effectiveness (EDGE) trial. J Rheumatol. 2007;34:408–20.

    CAS  PubMed  Google Scholar 

  6. Verma P, Prajapati SK, Yadav R, Senyschyn D, Shea PR, Trevaskis NL. Single intravenous dose of novel flurbiprofen-loaded proniosome formulations provides prolonged systemic exposure and anti-inflammatory effect. Mol Pharm. 2016;13(11):3688–99.

    Article  CAS  PubMed  Google Scholar 

  7. Motov S, Yasavolian M, Likourezos A, Pushkar I, Hossain R, Drapkin J, et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial. Ann Emerg Med. 2017;70(2):177–84.

    Article  PubMed  Google Scholar 

  8. Wang RD, Sheng XR, Guan WX, Wang M, Peng C, Yang YY, et al. Flurbiprofen axetil for postoperative analgesia in upper abdominal surgery: a randomized, parallel controlled, double-blind, multicenter clinical study. Surg Today. 2020. https://doi.org/10.1007/s00595-019-01951-1.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wladis EJ, Lee KW, De A. Intravenous ketorolac reduces pain score and opioid requirement in orbital surgery. Ophthalmic Plast Reconstr Surg. 2020;36(2):132–4. https://doi.org/10.1097/IOP.0000000000001484.

    Article  PubMed  Google Scholar 

  10. Brogden RN, Heel RC, Speight TM, Avery GS. Fenbufen: a review of its phar-macological properties and therapeutic use in rheumatic diseases and acute pain. Drugs. 1981;21:1–22.

    Article  CAS  PubMed  Google Scholar 

  11. Shinkai N, Korenaga K, Takizawa H, Mizu H, Yamauchi H. Percutaneous penetration of felbinac after application of transdermal patches: relationship with pharmacological effects in rats. J Pharm Pharmacol. 2008;60:71–6.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang C, Cui X, Yang Y, Gao F, Sun Y, Gu J, et al. Pharmacokinetics of felbinac after intravenous administration of felbinac trometamol in rats. Xenobiotica. 2011;41(4):340–8.

    Article  PubMed  Google Scholar 

  13. Cui Y, Lin X, Guan TT, Zhang Y, Tang X. A new rapid ultra-performance liquid chromatography method for the pharmacokinetic and bioavailability study of diclofenac sodium aqueous injection and lipid microsphere injection in rats. Biomed Chromatogr. 2010;24:406–12.

    CAS  PubMed  Google Scholar 

  14. Wu H, Chen Z, Sun G, Gu K, Pan Y, Hao J, et al. Intravenous flurbiprofen axetil can increase analgesic effect in refractory cancer pain. J Exp Clin Cancer Res. 2009;28:33.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Flurbiprofen. LiverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.

  16. World Medical Association Declaration of Helsinki. Recommendations guiding medical doctors in biomedical research involving human subjects. Ferney-Voltaire, France, 1989. Available from: https://fda.gov/oc/health/helsinki89.html. [Accessed 17 Aug 2007].

  17. World Health Organization. Handbook for good clinical research practice (GCP). Available from: https://www.who.int/medicines/. [Accessed 20 May 2020].

  18. Scheiman JM. NSAID-induced gastrointestinal injury: a focused update for clinicians. J Clin Gastroenterol. 2016;50(1):5–10.

    Article  CAS  PubMed  Google Scholar 

  19. Yeomans ND, Graham DY, Husni ME, Solomon DH, Stevens T, et al. Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial. Aliment Pharmacol Ther. 2018;47(11):1453–63.

    Article  CAS  PubMed  Google Scholar 

  20. Pratt V, McLeod H, Rubinstein W, Dean L, Kattman B, Malheiro A. Flurbiprofen therapy and CYP2C9 genotype. National Center for Biotechnology Information; 2012.

  21. Han MH, Nam JH, Noh E, Lee EK. Gastrointestinal risk of non-steroidal anti-inflammatory drugs and gastroprotective agents used in the treatment of osteoarthritis in elderly patients: a nationwide retrospective cohort study. Int J Clin Pharmacol Ther. 2019;57(11):531–41.

    Article  CAS  PubMed  Google Scholar 

  22. Fernandes E, Soares TB, Gonçalves H, Bernstorff S. A molecular biophysical approach to diclofenac topical gastrointestinal damage. Int J Mol Sci. 2018;19(11):3411.

    Article  PubMed Central  Google Scholar 

  23. US FDA. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. 2005. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf. [Accessed 2 Mar 2008].

  24. Takayama K, Hirose A, Suda I, Miyazaki A, Oguchi M, Onotogi M, et al. Comparison of the anti-inflammatory and analgesic effects in rats of diclofenac-sodium, felbinac and indomethacin patches. Int J Biomed Sci. 2011;7(3):222–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the volunteers enrolled in this trial, as well as the staff who contributed to this trial. The authors also express their gratitude to Mr. Jianfei Li (Clinical Project Manager at Shijiazhuang Yiling Pharmaceutical Co., Ltd.) for his contributions to the management of the trial.

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Authors and Affiliations

  1. Department of Phase I Clinical Trial Unit, The First Hospital of Jilin University, Changchun, 130021, Jilin, China

    Min Wu, Cuiyun Li, Hong Zhang, Jixuan Sun, Xiaoxue Zhu, Xiaojiao Li & Yanhua Ding

  2. Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, 050035, Hebei, China

    Xuedong Gao & Wei Wang

Authors
  1. Min Wu
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  2. Cuiyun Li
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  3. Hong Zhang
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  4. Jixuan Sun
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  5. Xiaoxue Zhu
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  6. Xiaojiao Li
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  7. Xuedong Gao
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  8. Wei Wang
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  9. Yanhua Ding
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Corresponding author

Correspondence to Yanhua Ding.

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Funding

This project was financially sponsored by the following programs: National Major Scientific and Technological Special Project for Significant New Drug Development during the Thirteenth Five-Year Plan Period of China (Project: 2017ZX09304004, 2017ZX09101001-002-004), the National Natural Science Foundation of China (Project: 81602897), the program for JLU Science and Technology Innovative Research Team (2017TD-08), and the Fundamental Research Funds for the Central Universities.

Conflict of Interest

Min Wu, Cuiyun Li, Hong Zhang, Jixuan Sun, Xiaoxue Zhu, Xiaojiao Li, Xuedong Gao, Wei Wang, Yanhua Ding and Li Liu have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

The clinical study protocol was approved by the Ethics Committee at the Jilin University First Affiliated Hospital-Clinical Research Institute in Changchun City, Jilin Province, China. Clinical procedures were conducted in the Phase I Clinical Trial Unit of the First Hospital of Jilin University. The studies (Registration Nos.: CTR20170496 and CTR20180896, https://www.chinadrugtrials.org.cn/) were conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice.

Informed consent

Written informed consent was obtained from each participant before the study commenced.

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Wu, M., Li, C., Zhang, H. et al. Pharmacokinetics, Safety, and Tolerability of Intravenous Felbinac Trometamol in Healthy Chinese Volunteers: A First-in-Human Single- and Multiple-Dose Escalation Phase I Study with a Randomized, Double-Blind, Placebo-Controlled Design. CNS Drugs 34, 867–877 (2020). https://doi.org/10.1007/s40263-020-00739-z

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  • DOI: https://doi.org/10.1007/s40263-020-00739-z

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