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THU0433 Pharmacodynamic and pharmacokinetic study of verinurad (RDEA3170) in adult male subjects with mild, moderate, and severe renal impairment: a phase 1, open-label study
  1. WB Smith1,
  2. J Hall2,
  3. JK Berg3,
  4. M Kazimir3,
  5. A Yamamoto2,
  6. S Walker4,
  7. C Lee2,
  8. TC Marbury5
  1. 1Volunteer Research Group, Knoxville, TN
  2. 2Ardea Biosciences, Inc., San Diego, CA
  3. 3DaVita Clinical Research, Minneapolis, MN
  4. 4Astrazeneca, Gaithersburg, MD
  5. 5Orlando Clinical Research Center, Orlando, FL, United States

Abstract

Background Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia.

Objectives This Phase 1, single-dose, open-label study investigated the pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in adult subjects with mild, moderate, or severe renal impairment and matched controls with normal renal function (NCT02219516).

Methods Adult males aged 18–85 years were enrolled with a screening serum uric acid (sUA) 4.5–10 mg/dL and creatinine clearance calculated by Cockcroft-Gault formula of 60 to <90 mL/min (mild renal impairment), 30 to <60 mL/min (moderate impairment), 15 to <30 mL/min (severe impairment), or ≥90 mL/min (matched controls). Oral verinurad 15 mg was administered once under fasted conditions. Serial blood and urine samples were taken 30 min before and up to 72 hours postdose. Safety assessments included laboratory, ECG, and vital sign parameters as well as adverse event (AEs) reporting.

Results PD data were based on 7–8 subjects per group. Verinurad decreased sUA in all groups, with greatest changes in the normal function and mild renal impairment groups. Mean (SD) maximal % change in sUA from baseline (Emax) was -38.3 (14.8)%, -36.9 (13.6)%, -20.5 (6.64)%, and -12.6 (6.94)%, respectively, in the normal function and mild, moderate, and severe renal impairment groups. Increase in the amount of excretion of uric acid due to verinurad treatment decreased in subjects with moderate and severe renal impairment. Plasma Cmax and AUC of verinurad increased with decreasing renal function. Verinurad at the 15 mg dose was well tolerated, with no serious AEs, no subject withdrawals due to AEs, and no Renal Events Adjudication Committee (REAC)-adjudicated renal events during treatment. One patient in each renal impairment group had treatment-emergent AEs considered possibly related to verinurad, which were categorized as gastrointestinal in nature. There were no clinically meaningful changes noted in laboratory values or vital signs.

Conclusions The sUA lowering effect of verinurad was observed across the spectrum of renal function. Consistent with the verinurad renal-dependent mechanism of action, decreasing sUA lowering was demonstrated with increasing renal impairment. Verinurad safety and tolerability were similar across all stages of renal impairment.

Disclosure of Interest W. Smith Employee of: Volunteer Research Goup, J. Hall Employee of: Ardea Biosciences, Inc., J. Berg Employee of: DaVita Clinical Research, M. Kazimir Employee of: DaVita Clinical Research, A. Yamamoto Employee of: Ardea Biosciences, Inc., S. Walker Employee of: AstraZeneca, C. Lee Employee of: Ardea Biosciences, Inc., T. Marbury Employee of: Orlando Clinical Research Center

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