Supratherapeutic dose evaluation and effect of lesinurad on cardiac repolarization: a thorough QT/QTc study
Authors Shen Z, Gillen M, Tieu K, Nguyen M, Harmon E, Wilson DM, Kerr B, Lee CA
Received 7 June 2016
Accepted for publication 4 August 2016
Published 27 October 2016 Volume 2016:10 Pages 3509—3517
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Lucy Goodman
Peer reviewer comments 3
Editor who approved publication: Dr James Janetka
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. A maximum 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 800 mg, 1,200 mg, and 1,600 mg. 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 1,600 mg (supratherapeutic dose), lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours 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 <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, 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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