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Zancong Shen,1 Michael Gillen,2 Kathy Tieu,1 Mai Nguyen,1 Erin Harmon,1 David M Wilson,1 Bradley Kerr,1 Caroline A Lee1 1Ardea Biosciences, Inc., San Diego, CA, 2AstraZeneca LP, Gaithersburg, MD, USA Introduction: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. Amaximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization.Methods: The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve) was determined at doses of 800mg, 1,200mg, and 1,600mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600mg (supratherapeutic dose), lesinurad 400mg, moxifloxacin 400mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI).Results: The upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI) was 480ms or QTcI increases >30ms were observed. Moxifloxacin mean QTcI intervals were >5ms, and the lower bounds of the 90% confidence interval were >5ms at 2hours, 3hours, and 4hours, confirming assay sensitivity.Conclusion: Lesinurad, at supratherapeutic doses, does not have a significant effect on the QT interval in healthy male or female subjects. Keywords: pharmacokinetics, maximum tolerated dose study, QT interval, selective uric acid reabsorption inhibitor

The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans.The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [14C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%.The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]lesinurad dose.Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites 14C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [14C]lesinurad dose. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites

To the Editor: Leprosy (Hansen disease) is caused by Mycobacterium leprae, an extremely slow-growing, intracellular, acid-fast bacillus with a typical incubation period >2–5 years, ranging up to 20 years. Anesthetic, thickened skin lesions and granulomatous inflammation in biopsy specimens are typical findings because direct visualization of the organism from biopsy specimens is unreliable (1). The worldwide prevalence of leprosy is estimated to be