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Clin Pharmacol Drug Dev. 2018 Mar;7(3):332-340. doi: 10.1002/cpdd.393. Epub 2017 Oct 11.

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals.

Author information

1
Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT, USA.
2
Lundbeck, Deerfield, IL, USA.
3
Section of Cardiac Electrophysiology, The Center for Comprehensive Cardiovascular Care, St. Louis University Hospital and School of Medicine, St. Louis, MO, USA.

Abstract

A double-blind, 4-period crossover study (NCT01327066) was conducted to assess the effect of the novel norepinephrine prodrug droxidopa on the QT interval in in healthy subjects. Subjects were randomized to receive a single dose of droxidopa 600 mg (maximal dose) and 2000 mg (supratherapeutic dose) compared with the positive control, moxifloxacin 400 mg, and placebo, each separated by a 3-day washout period. Patients were monitored by continuous Holter monitoring, and electrocardiograms (ECGs) were extracted 0.5-23 hours after dosing. Blood samples for pharmacokinetic analysis were collected before dosing and after ECG data collection. The primary end point was the time-matched placebo-adjusted change from baseline in the individually corrected QT (QTcI). The time-averaged QTcI mean placebo-corrected changes from baseline for droxidopa 600 and 2000 mg were 0.1 milliseconds (90%CI, -0.9 to 1.0 milliseconds) and 0.3 milliseconds (90%CI, -0.6 to 1.3 milliseconds), respectively, and 9 milliseconds (90%CI, 8.4-10.3 milliseconds) for moxifloxacin. This study found no effect of either dose of droxidopa on cardiac repolarization using QTcI. Analysis of the pharmacokinetic/pharmacodynamic relationship and cardiac repolarization showed no association with droxidopa exposure. There were no clinically relevant effects of droxidopa on heart rate, atrioventricular conduction, or cardiac depolarization identified. No morphologic ECG changes were observed.

KEYWORDS:

QTc interval; cardiac repolarization; cardiovascular safety; droxidopa; neurogenic orthostatic hypotension; pharmacodynamics; pharmacokinetics

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