Background Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia.
Objectives The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad following single and multiple doses in healthy adult males.
Methods This was a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Panels of 8 male subjects (6 active, 2 placebo) received a single oral dose of verinurad or placebo in either a fasted (2 mg, 5 mg, 20 mg, 40 mg) or fed (5 mg, 20 mg) state and panels of 12 male subjects (9 active, 3 placebo) received ascending doses of once-daily verinurad (1 mg, 5 mg, and 10 mg) or placebo in a fasted state for up to 10 days. Verinurad was administered as an oral solution for 1 and 2 mg doses and in tablet form for doses >2 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid at predetermined time points. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs).
Results A total of 81 adult males aged 18–54 years enrolled and completed the study. Following single oral doses of verinurad, absorption was rapid and exposure (maximum plasma concentration [Cmax] and area under the plasma concentration-time curve [AUC]) increased in a dose-proportional manner up to the maximum dose tested; Cmax was achieved at 0.5–0.75 hours post-dose in the fasted state, and was slightly delayed to 1.25 hours post-dose in the fed state. Food appeared to decrease AUC by about 23% and Cmax by about 50%. Following multiple daily doses, there was modest accumulation of verinurad. Urinary excretion of verinurad accounted for approximately 2% of the administered dose, suggesting that renal excretion is a minor elimination pathway for unchanged verinurad. Reductions in serum uric acid (sUA) correlated with dose. Under fasted conditions, single-dose administration of verinurad 2, 5, 20, or 40 mg reduced sUA levels by 16%, 24%, 48%, and 62%, respectively. Following multiple once-daily dosing for 10 days, verinurad reduced sUA levels by 22%, 44%, and 61% for the 1, 5, and 10 mg doses, respectively. A persistent pharmacologic effect (>15% fractional excretion of uric acid relative to baseline) was evident for at least 24 hours after dosing for verinurad doses of 2 mg or above. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs or clinically significant laboratory or ECG abnormalities were reported.
Conclusions Single and multiple doses of verinurad were well tolerated, absorption was rapid and exposure was dose-proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in sUA. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.
Acknowledgements The authors thank Caroline Lee of Ardea Biosciences, Inc. for critical review of the abstract.
Disclosure of Interest M. Gillen Employee of: AstraZeneca, Z. Shen Employee of: Ardea Biosciences, Inc., J. Miner Employee of: Ardea Biosciences, Inc.