title: 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.
authors.affiliation: Exploratory Clinical Development, Novartis Pharmaceuticals Corporation, 435/1159, One Health Plaza, East Hanover, NJ 07936-1080, USA.
authors.forename: Denise B
authors.initials: DB
authors.lastname: Serra
authors.forename: Melton B
authors.initials: MB
authors.lastname: Affrime
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bedigian
authors.forename: Gerard
authors.initials: G
authors.lastname: Greig
authors.forename: Slavica
authors.initials: S
authors.lastname: Milosavljev
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000032:analysis; D003915:Dextromethorphan / Q000097:blood; D003917:Dextrorphan / Q000097:blood; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D014549:Urinary Incontinence / Q000188:drug therapy*
chemical_list: D001572:Benzofurans; D011759:Pyrrolidines; D043587:Receptor, Muscarinic M3; D003917:Dextrorphan; D003915:Dextromethorphan; D004247:DNA; C101207:darifenacin; D019389:Cytochrome P-450 CYP2D6