AB0886 Pharmacokinetics, pharmacodynamics, and tolerability of verinurad (RDEA3170), a selective uric acid reabsorption inhibitor, in healthy adult male subjects
Authors: M Gillen, Z Shen, JN Miner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. <h3>Objectives</h3> The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad following single and multiple doses in healthy adult males. <h3>Methods</h3> 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 &gt;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). <h3>Results</h3> 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 [C<sub>max</sub>] and area under the plasma concentration-time curve [AUC]) increased in a dose-proportional manner up to the maximum dose tested; C<sub>max</sub> 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 C<sub>max</sub> 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 (&gt;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. <h3>Conclusions</h3> 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. <h3>Acknowledgements</h3> The authors thank Caroline Lee of Ardea Biosciences, Inc. for critical review of the abstract. <h3>Disclosure of Interest</h3> M. Gillen Employee of: AstraZeneca, Z. Shen Employee of: Ardea Biosciences, Inc., J. Miner Employee of: Ardea Biosciences, Inc.