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Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects.

Ayalasomayajula, Surya and Yeh, Ching-Ming and Vaidyanathan, Sujata and Flannery, Brian and Dieterich, Hans Armin and Howard, Danny and Bedigian, Martin and Dole, William (2008) Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects. Journal of Clinical Pharmacology, 48 (7). pp. 799-811. ISSN 0091-2700

Abstract

This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Aliskiren; moxifloxacin; QT interval; cardiac repolarization
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Date Deposited: 14 Dec 2009 13:54
Last Modified: 31 Jan 2013 01:06
URI: https://oak.novartis.com/id/eprint/785

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