Silodosin Demonstrates No Meaningful Effects on Heart Rate or QTc Interval Duration: Presented at AUA

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Title: Silodosin Demonstrates No Meaningful Effects on Heart Rate or QTc Interval Duration: Presented at AUA
URL: http://www.pslgroup.com/dg/2225A6.htm
Doctor's Guide
May 28, 2008

By Deborah Brauser

ORLANDO, Fla -- May 27, 2008 -- Silodosin, an investigative alpha-blocker treatment for benign prostatic hyperplasia (BPH), has no meaningful adverse effects on heart rate, PR and QRS interval duration, or cardiac repolarisation, according to research presented here at the Annual Meeting of the American Urological Association (AUA).

Herbert Lepor, MD, Professor and Chair, Department of Urology, New York University School of Medicine, New York, New York, reported the results in a presentation here on May 21.

"Since 2005, the [US Food and Drug Administration] has required that all new drugs must be scrutinised for QTc interval, which was the purpose of this test -- to focus on silodosin's electrocardiographic effects," said Dr. Lepor.

This cardiac safety trial was a double-blind, randomised, parallel-group study designed to compare the QTc effects of therapeutic and supratherapeutic doses of silodosin versus placebo and versus moxifloxacin using an electrocardiogram (ECG).

A total of 186 healthy men, ranging in age from 18 to 45 years, were randomised to receive 8 or 24 mg of silodosin or placebo for 5 days, or 400 mg of moxifloxacin once only on day 5, followed by individual heart rate QTc measurements for all patients. The central ECG laboratory was blinded to treatment.

Using a Mortara Instrument H12 Plus continuous 12-lead ECG digital recorder, 5 ECGs were extracted within a 1- to 3-minute window at baseline and on day 5 at the following times relative to dosing: -0.25, 1, 1.5, 2, 3, 4, 6, 8, 10, and 23.5 hour. Plasma was also sampled for analysis of silodosin and metabolites.

Results from the time-matched analysis of all individual corrected QT (QTcI) end points revealed no upper bounds greater than 10 ms. "In fact, all were consistently below that marker," said Dr. Lepor.

The QTcI change from baseline was similar for silodosin and placebo. For clinical and supratherapeutic doses of silodosin, the changes were -2.7 and 1.4 ms, respectively, while the placebo was measured at -0.8 ms. Moxifloxacin was 4.0 ms.

Outlier analysis, morphological review, and pharmacokinetic-pharmacodynamic modelling showed no meaningful effects.

In addition, no statistically significant correlation was observed for maximum plasma concentration and QTcI change for silodosin or metabolites.

"[Silodosin] is a new highly selective alpha-blocker," said Dr. Lepor. In patients at risk for QTc interval prolongation, as clinicians, "we need to judge new drugs on these safety issues," he added.

Funding for this trial was provided by Watson Laboratories, Inc.

[Presentation title: Double-Blind, Randomized, Parallel-Group Study to Define Electrocardiographic Effects of Silodosin, a Uroselective Alpha-Adrenergic Antagonist. Abstract 2037]

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