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Zancong Shen,1 Michael Gillen,2 Jeffrey N Miner,1 Gail Bucci,1 David M Wilson,1 Jesse W Hall1 1Ardea Biosciences, Inc., San Diego, CA, 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males.Subjects and methods: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs).Results: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5–0.75hours and 1.25hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40mg, single dose) and 61% (10mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6hours after dosing and was still evident ≥24hours for verinurad doses ≥2mg. 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.Conclusion: 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 serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout. Keywords: fractional excretion of uric acid, selective uric acid reabsorption inhibitor, serum urate, urinary uric acid&nbsp

Zancong Shen, Colin Rowlings, Brad Kerr, Vijay Hingorani, Kimberly Manhard, Barry Quart, Li-Tain Yeh, Chris Storgard Ardea Biosciences, Inc. (a member of the AstraZeneca group), San Diego, CA, USA Abstract: Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration–time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. Arelative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated. Keywords: urinary excretion, urate lowering, URAT1, single and multiple doses, food effect, clearance&nbsp