Darifenacin, an M-3, Selective Receptor Antagonist (M-3 Sra), Does Not Prolong Qt/Qtc.

Background/Aims Darifenacin, an M3 SRA developed for the treatment of overactive bladder (OAB), was assessed for its effect on QT/QTc interval. Methods This thorough QT study was a 7-day, parallel-group, randomized study in 188 healthy subjects treated once daily with: darifenacin (15mg, maximum proposed marketed dose, n=47; and 75mg, supratherapeutic dose, n=46), moxifloxacin 400mg (positive control, n=48), or placebo (n=47). Standard 12-lead ECGs were collected digitally in triplicate on days -1 and 6 at 13 predefined timepoints. QT intervals were corrected for heart rate (QTc) using Fridericia's formula. QTc change from baseline was compared between on-drug and placebo within ANCOVA. Results Darifenacin up to 75mg once daily did not prolong QTc interval compared with placebo. Mean difference at Tmax was −0.4ms for darifenacin 15mg (90% CI −4.1,3.2; p=0.842) and −2.2ms for darifenacin 75mg (CI −6.6, 2.2; p=0.4). Moxifloxacin resulted in a significant increase in QTc versus placebo (+11.6ms, CI 7.6,15.5; p<0.001). Aside from the expected antimuscarinic complaints of constipation and dry mouth reported by several subjects at D 75mg, the treatments were safe and well tolerated. Conclusions Darifenacin did not prolong QTc interval even at a dose 5x the maximum proposed marketed dose. Darifenacin can therefore be expected not to contribute to the risk of torsade de pointes in the OAB patient population encountered in clinical practice. Clinical Pharmacology & Therapeutics (2005) 77, P10–P10; doi: 10.1016/j.clpt.2004.11.040