QT and QTc Interval With Standard and Supratherapeutic Doses of Darifenacin, a Muscarinic M₃ Selective Receptor Antagonist for the Treatment of Overactive Bladder

Abstract

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drug's ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7-day, randomized, parallel-group study (n=188) measured QT/QTc interval in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. There was no significant increase in QTcF interval with darifenacin treatment compared with placebo. Mean changes from baseline at pharmacokinetic Tmax versus placebo were -0.4 and -2.2 milliseconds in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 milliseconds in the moxifloxacin group (P<.01). This study demonstrates that darifenacin does not prolong QT/QTc interval.

Effect of brivaracetam on cardiac repolarisation – a thorough QT study

“…The results for maximum ÁÁQTc F were comparable. The QTc prolongation observed with moxifloxacin was in the range of those reported in other studies [21][22][23][24][25] . Lengthening of QTc after moxifloxacin compared to placebo was observed as soon as 1 h after dosing and continued until the last timepoint at 12 h post-dose.…”

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

“…7 Published literature on TQT studies tend to use both therapeutic and supratherapeutic doses in the characterization of cardiac repolarization effects. [10][11][12][13][14][15][16] Recently, Iwamoto et al 10 sufficient in the data analysis. 10 In addition, in cases where there appears to be an effect of a drug on QT interval, considerable added value can be gained by characterizing the concentration-QT relationships in a quantitative fashion to provide interpretations whether the observed effects are clinically meaningful.…”

How to choose the initial drug treatment for overactive bladder

“…A number of agents, including the anticholinergic terodiline, have been withdrawn due to prolongation of the QT interval. In a 7-day, randomized, placebo-controlled study (n = 188), darifenacin 15 and 75 mg did not show any effect on QT interval [31]. Similarly, prolongation of the QT interval has not been shown to occur with trospium chloride.…”