Prolongation of QT /QTc interval on a surface electrocardiogram (ECG) reflects delayed cardiac repolarization and is a predictor of a drug’s tendency to cause potentially fatal ventricular tachyarrhythmia (torsade de pointes). The risk of such drug-induced arrhythmia is a particular concern in females, older patients and patients taking more than one medication. This study evaluated the effects on QT /QTc interval of darifenacin, an M₃ SRA developed for the treatment of overactive bladder (OAB). OAB is a debilitating condition characterized by the symptoms of urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia. Since OAB is particularly prevalent among older people , a group at increased risk of drug-induced torsade de pointes and cardiovascular co-morbidities, it is essential that OAB treatments do not cause QT /QTc prolongation.

This 7 day, randomized study in healthy subjects (n = 188, 56% female, mean age 44 years) involved four parallel treatment groups: darifenacin 15 mg once daily (maximum proposed marketed dose, n = 47), darifenacin 75 mg once daily (n = 46), moxifloxacin 400 mg once daily (n = 48), and placebo (n = 47). Owing to darifenacin’s dual metabolism by CYP3A4 and CYP2D6, which is polymorphic in the general population, subjects with low intrinsic CYP2D6 activity were included (n = 32, 17%) in order to represent a complete range of darifenacin exposures. Moxifloxacin, a fluoroquinolone antibacterial agent known to prolong QT /QTc interval by 5–10 ms at the recommended dose of 400mg, was used as a positive control. Standard 12-lead ECGs were collected digitally on days –1 and 6 at 13 predefined timepoints. Blood samples were collected each day predose and on day 6 at 14 predefined timepoints. QT intervals were corrected for heart rate (QTc) using Fridericia’s formula.

Darifenacin up to 75 mg once daily (five times the maximum proposed marketed dose) did not prolong QTc interval compared with placebo (Table 1). In contrast, moxifloxacin treatment resulted in a significant increase in QTc vs placebo (+11.6 ms; p < 0.001). QT /QTc results for CYP2D6 poor metabolizers were consistent with those for the study population as a whole; QTc mean change from baseline vs placebo at t_max with darifenacin 75 mg in poor metabolizers (n = 7) was –1.8 ms.

Table 1:
Mean change from time-averaged baseline (day –1) vs placebo.
Mean difference from placebo (ms) (SEM).

* p < 0.001 vs placebo

This study demonstrates that darifenacin does not prolong QTc interval, even at the supra-therapeutic dose of 75 mg (five times the maximum proposed marketed dose). Darifenacin can therefore be expected not to contribute to the risk of torsade de pointes in the diverse OAB patient population encountered in clinical practice.