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Original article
Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
  1. Roy Fleischmann1,
  2. Peter Winkle2,
  3. Jeffrey N Miner3,
  4. Xiaohong Yan3,
  5. Liz Hicks3,
  6. Shakti Valdez3,
  7. Jesse Hall3,
  8. Sha Liu,
  9. Zancong Shen3,
  10. Michael Gillen4 and
  11. Martha Hernandez-Illas5
  1. 1Metroplex Clinical Research Center, University of Texas, SW Medical Center, Dallas, Texas, USA
  2. 2Anaheim Clinical Trials, Anaheim, California, USA
  3. 3Ardea Biosciences, San Diego, California, USA
  4. 4AstraZeneca LP, Gaithersburg, Maryland, USA
  5. 5QPS MRA (Miami Clinical Research), Miami, Florida, USA
  1. Correspondence to Dr Roy Fleischmann; rfleischmann{at}arthdocs.com

Abstract

Objectives Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout.

Methods Forty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid.

Results Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes.

Conclusion Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout.

Trial registration number NCT02498652.

  • gout
  • pharmacokinetics
  • treatment

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors All the authors contributed to the acquisition, analysis, interpretation of data for the work, drafting the work or revising it critically for important intellectual content and final approval of the version to be published. JNM, JH and MG were involved in the conception and design of the work

  • Funding Funding for this study was provided by Ardea Biosciences/AstraZeneca.

  • Competing interests RF received a clinical study grant from Ardea Biosciences. PW is a full-time employee of Anaheim Clinical Trials. JNM, XY, LH, SV, JH, SL and ZS are/were full-time employees of Ardea Biosciences, a member of the AstraZeneca Group. MG is a full-time employee of AstraZeneca. MHI reports no conflict of interest.

  • Patient consent Obtained.

  • Ethics approval Schulman Associates IRB, Cincinnati, Ohio, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement De-identified patient data from this study are made available for scientific research on a case by case basis through AstraZeneca’s Data Request Portal: https://astrazenecagroup-dt.pharmacm.com//DT/Home/Index/