| الوصف: |
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 |
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