Hara, Hisanori, Sechaud, Romain, Uziel-Fusi, Susan, Drollmann, Anton Franz and winkle, peter (2013) Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three-period, cross-over, placebo- and positive-controlled study. Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three-period, cross-over, placebo- and positive-controlled study .

Abstract

Objective
Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects.
Methods
This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supratherapeutic dose (8-fold clinical dose in COPD patients) of 400 μg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazett-corrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability.
Results
A total of 73 healthy male (N = 35) and female (N = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 min, with the upper limit of the two-sided 90% CI being 4.80 ms, excluding a relevant QT-effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of –2.88 (90% CI: –3.78, –1.99) beats per min (bpm) over whole time range and a maximum of –5.87 (90% CI: –7.82, –3.92) bpm at 5 h post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median Tmax = 7 min). All the treatments were well tolerated with no serious adverse events.
Conclusion
A supratherapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.

Item Type:	Article
Date Deposited:	02 May 2016 23:45
Last Modified:	02 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/20159