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A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia

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Abstract

Background and Objective

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor that is being developed for the treatment of hyperuricemia and gout. The primary aim of the present study was to study the pharmacokinetic drug‒drug interactions (DDIs) of HP501, febuxostat, and colchicine in hyperuricemic patients.

Methods

Hyperuricemic patients were randomly divided into group A, receiving HP501 40 mg once daily on days 1 and 4–10, and group B, receiving febuxostat 40 mg once daily on day 1 and HP501 40 mg plus febuxostat 40 mg on days 4–10. All patients received 0.5 mg colchicine once daily from day 4 to 12. Blood samples were collected for measurement of drug concentrations and serum uric acid (sUA) levels.

Results

Coadministration of colchicine with HP501 or HP501 plus febuxostat did not affect steady-state exposure to colchicine. Coadministration of HP501 and febuxostat did not significantly change the pharmacokinetic profiles of either drug. Following multiple administrations of HP501 40 mg once daily for 7 days, the maximal percent sUA change from baseline in group A was − 24.77%. The coadministration of HP501 40 mg and febuxostat 40 mg in group B for 7 days resulted in a − 55.82% maximal sUA reduction from baseline, and all patients achieved the goal of sUA < 360 μmol/L. All adverse events (AEs) were either mild or moderate, and the most frequently reported AEs were diarrhea and elevated alanine aminotransferase (ALT) levels.

Conclusions

The concomitant use of HP501, febuxostat, and colchicine did not produce clinically meaningful DDIs in terms of their pharmacokinetic properties.

Clinical Trial Registration

No. CTR20212261 (http://www.chinadrugtrials.org.cn/) registered September 2021.

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References

  1. Lin Y, Chen X, Ding H, Ye P, Gu J, Wang X, et al. Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperursicaemia: a randomized controlled phase II study. Rheumatology. 2021;60:5089–97. https://doi.org/10.1093/rheumatology/keab198.

    Article  CAS  PubMed  Google Scholar 

  2. Hosoya T, Furuno K, Kanda S. A clinical pharmacology study of the novel, selective urate reabsorption inhibitor dotinurad in outpatients. Clin Exp Nephrol. 2020;24:103–11. https://doi.org/10.1007/s10157-020-01857-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kumagai T, Ota T, Tamura Y, Chang WX, Shibata S, Uchida S. Time to target uric acid to retard CKD progression. Clin Exp Nephrol. 2017;21:182–92. https://doi.org/10.1007/s10157-016-1288-2.

    Article  CAS  PubMed  Google Scholar 

  4. Li L, Zhang Y, Zeng C. Update on the epidemiology, genetics, and therapeutic options of hyperuricemia. Am J Transl Res. 2020;12:3167–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020;16:380–90. https://doi.org/10.1038/s41584-020-0441-1.

    Article  PubMed  Google Scholar 

  6. Kumar S, Ng J, Gow P. Benzbromarone therapy in management of refractory gout. N Z Med J. 2005;118:U1528.

    PubMed  Google Scholar 

  7. Deeks ED. Lesinurad: A review in hyperuricaemia of gout. Drugs Aging. 2017;34:401–10. https://doi.org/10.1007/s40266-017-0461-y.

    Article  CAS  PubMed  Google Scholar 

  8. Tausche AK, Alten R, Dalbeth N, Kopicko J, Fung M, Adler S, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study. Rheumatology. 2017;56:2170–8. https://doi.org/10.1093/rheumatology/kex350.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Z, Li X, Jin Y, Liu R, Di X, Zhou Y, et al. Safety, efficacy, and pharmacokinetics of HP501 in healthy volunteers and hyperuricemic patients: a phase I/IIa study. J Clin Endocrinol Metab. 2022;107:1667–78. https://doi.org/10.1210/clinem/dgac032.

    Article  PubMed  Google Scholar 

  10. Yu Y, Wang D, Zhou Q, Wang C, Ma X, Gao Y, et al. Recommendations in clinical practice guidelines on gout: systematic review and consistency analysis. Clin Exp Rheumatol. 2020;38(5):964–72.

    PubMed  Google Scholar 

  11. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29–42. https://doi.org/10.1136/annrheumdis-2016-209707.

    Article  CAS  PubMed  Google Scholar 

  12. Li L, Zhu X, Dai Y. Chinese mlti-disciplinary consensus on the diagnosis and treatement of hyperuricemia and its related disease. Chin J Intern Med. 2017;56:235–48. https://doi.org/10.3760/cma.j.issn.0578-1426.2017.03.021.

    Article  Google Scholar 

  13. Dalbeth N, Jones G, Terkeltaub R, Khanna D, Fung M, Baumgartner S, et al. Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study. Arthritis Res Ther. 2019;21:8. https://doi.org/10.1186/s13075-018-1788-4.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017;69:1903–13. https://doi.org/10.1002/art.40159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fleischmann R, Kerr B, Yeh LT, Suster M, Shen Z, Polvent E, et al. Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia. Rheumatology. 2014;53:2167–74. https://doi.org/10.1093/rheumatology/ket487.

    Article  CAS  PubMed  Google Scholar 

  16. Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC Geriatr. 2012;12:11. https://doi.org/10.1186/1471-2318-12-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52:916–23. https://doi.org/10.1002/art.20935.

    Article  CAS  PubMed  Google Scholar 

  18. Gasparyan AY, Ayvazyan L, Yessirkepov M, Kitas GD. Colchicine as an anti-inflammatory and cardioprotective agent. Expert Opin Drug Metab Toxicol. 2015;11:1781–94. https://doi.org/10.1517/17425255.2015.1076391.

    Article  CAS  PubMed  Google Scholar 

  19. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497–505. https://doi.org/10.1056/NEJMoa1912388.

    Article  CAS  PubMed  Google Scholar 

  20. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62:1060–8. https://doi.org/10.1002/art.27327.

    Article  CAS  PubMed  Google Scholar 

  21. Tardif JC, Bouabdallaoui N, L’Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9:924–32. https://doi.org/10.1016/s2213-2600(21)00222-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hu M, Tomlinson B. Febuxostat in the management of hyperuricemia and chronic gout: a review. Ther Clin Risk Manag. 2008;4:1209–20. https://doi.org/10.2147/tcrm.s3310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Belhocine M, Mourad A, Chapdelaine A, Mansour AM, Troyanov Y, Doré M. Optimizing thiopurine therapy with a xanthine oxidase inhibitor in patients with systemic autoimmune diseases: a single-centre experience. Can J Hosp Pharm. 2021;74:361–9. https://doi.org/10.4212/cjhp.v74i4.3199.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Patel AV, Gaffo AL. Managing gout in women: current perspectives. J Inflamm Res. 2022;15:1591–8. https://doi.org/10.2147/JIR.S284759.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors wish to thank all the participating patients and their families.

Author information

Author notes

  1. Ruilin Ding, Longxia Chen have contributed equally.

Authors and Affiliations

  1. Institute of Drug Clinical Trial/GCP Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Ruilin Ding, Longxia Chen, Tengqiong Xiong, Hong Chen, Xiaojing Hu & Yun Li

  2. Hinova Pharmaceuticals Inc., Chengdu, Sichuan, China

    Xinghai Li & Yi Zhou

  3. Department of Psychiatry, The Affiliated Hospital of Southwest Medical University, Luzhou, China

    Kezhi Liu

  4. Department of Rheumatology, Dazhou Central Hospital, Dazhou, Sichuan, China

    Jianhong Wu

  5. Department of Cardiology, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, 646000, China

    Feng Jiang & Qing Peng

Authors
  1. Ruilin Ding
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Corresponding authors

Correspondence to Feng Jiang or Qing Peng.

Ethics declarations

Funding

This study was sponsored by Hinova Pharmaceuticals Inc. (Chengdu, China).

Conflicts of Interest

Xinghai Li and Yi Zhou are employees of Hinova Pharmaceuticals Inc. The other authors declare no conflicts of interest.

Ethics Approval

The study protocol and informed consent forms were reviewed and approved by the institutional ethics committee of the Affiliated Hospital of Southwest Medical University (Luzhou, China, approval number: L2021027). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Consent to Participate

All participants provided written informed consent before participation in the study.

Consent to Publish

Not applicable.

Availability of Data and Material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Author Contributions

Study conception and/or design: QP, XL, FJ. Data acquisition: RD, LC, TX, HC, XH, YL, KL, JW. Data analysis: RD, LC, XL. Interpretation of results: RD, LC, XL, YZ, QP. All authors were involved in the review and approval of the manuscript and in the decision to submit the article for publication. All authors also confirm accountability for the accuracy and integrity of the work.

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Ding, R., Chen, L., Li, X. et al. A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia. Clin Drug Investig 43, 401–411 (2023). https://doi.org/10.1007/s40261-023-01274-7

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  • DOI: https://doi.org/10.1007/s40261-023-01274-7

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