New erectile dysfunction drugs pass QT tests: not clinically relevant.
The consensus was reached on separate unanimous votes. Since the panel's decision, the FDA has approved alfuzosin (UroXatral), a selective [[alpha].sub.1]-adrenergic blocker for the treatment of benign prostatic hypertrophy. Alfuzosin has been marketed in Europe since 1987 and is approved in 108 countries. The manufacturer, Sanofi-Synthelabo, said that alfuzosin would be available in the United States in the second half of 2003.
At press time, the FDA had not yet approved vardenafil (Levitra), a phosphodiesterase type 5 (PDE 5) inhibitor used to treat erectile dysfunction. Vardenafil has been approved in 34 other countries since March 2003. According to its manufacturer, the Bayer Corp., vardenafil has greater potency and selectivity for PDE 5 than does sildenafil (Viagra), also a PDE 5 inhibitor.
Prolongation of the QT interval, an electrocardiographic sign of delayed cardiac repolarization, has been associated with susceptibility to the potentially fatal ventricular arrhythmia torsades de pointes. Before considering the drugs for approval, the FDA asked the manufacturers to conduct more studies as part of an expanded review of the QT-prolonging effects.
Both manufacturers studied the effects of single doses of the drugs on the "corrected" QT (QTc) interval in healthy men. Since alfuzosin and vardenafil increase heart rate, and the QT interval is highly dependent on heart rate, various methods were used to correct for heart rate changes. The methods included the traditional, most widely used methods, the Bazett's, which experts at the meeting said overcorrected for heart rate, and Fridericia's method. Newer less-well-tested methods also were used in these studies, including a Holter monitoring method that the panel agreed was promising.
A 400-mg dose of moxifloxacin, a quinolone antibiotic marketed as Avelox by Bayer, served as a positive control to test the correction method's sensitivity; moxifloxacin is known to cause modest QT-interval prolongation (greater than 5-10 milliseconds), but to date has not been linked with ventricular arrhythmias.
In the alfuzosin crossover study, 48 healthy men aged 19-45 years were given a single dose of 10 mg of alfuzosin (the therapeutic dose), a supratherapeutic dose of 40 mg, or moxifloxacin. (See chart.)
The company noted that the increase at four times the therapeutic dose was less than half the increase observed with therapeutic doses of moxifloxacin-and below the range suspected of being associated with torsades de pointes, based on a draft FDA document. According to the FDA, drug-related increases in the mean QT/QTc interval of 5-10 milliseconds have not been clearly associated with torsades de pointes; increases of 10-20 milliseconds "are of some concern but have been approved if they appear to have important therapeutic roles." Drugs that cause increases above 20 milliseconds have "a substantially increased likelihood of being proarrhythmic."
Corroborating these data is the absence of a signal for ventricular arrhythmias in the clinical trial database (more than 2,000 patients who were men older than aged 65, 40% of whom had cardiovascular disease) or in the postmarketing database (more than 130,000 similar patients), according to Sanofi.
Panel chair Dr. Jeffrey Borer, director of the division of cardiovascular pathophysiology at Cornell University, New York, said he felt "reasonably assured" that the changes were not clinically relevant, considering that me dose mat wm de used clinically was compared with a supratherapeutic dose and with moxifloxacin. The QTc findings with the relatively high 40-mg dose appeared to be "less impressive" than those seen with moxifloxacin, which does not appear to have been associated "with some overwhelming frequency of horrible events," he remarked.
In the vardenafil study of 50 healthy men, aged 45-60, the peak mean effect of 5-10 milliseconds was similar to that seen with sildenafil, according to the company. Sildenafil has not been shown to increase cardiovascular events when compared with an age-matched general population. In studies of vardenafil, there was no evidence of drug-induced torsades de pointes and related cardiovascular events. This study employed a subject-specific correction method that, according to Sanofi, is not optimal but is more precise and less likely to overcorrect the QT interval than are the Bazett's and Fridericia's methods.
Dr. Borer said that at least at 10 mg, the dose of vardenafil most likely to be used, the effect on QT/QTc was less than the effect seen with moxifloxacin, which he again observed has not been shown to be associated with important arrhythmic event risk.
Asked whether any one approach to correction of the QT changes was more valid than others, the panel essentially agreed that there was not enough information at this time to determine whether the results of any one correction method were better than the others.
The studies did not test a population of older men with a high rate of cardiovascular disease, who will be the likely candidates for the drugs. The panel acknowledged, however, that these are the best studies of drug effects on QT intervals conducted to date.
The panel did not recommend studies of QT-interval effects of previously approved drugs in the same classes.
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|Publication:||Internal Medicine News|
|Date:||Sep 1, 2003|
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