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

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.

Methods of Subject‐Specific Heart Rate Corrections

“…3 The socalled individual heart corrections (providing the QTcI intervals) that reflect the subject-specific QT/RR relationship are presently used in a number of studies. [4][5][6] Most of the studies using the individual corrections follow the design of the very first study that utilized QTcI values. 7 In that study, QT and RR readings of drug-free data points were taken in each subject separately.…”

“…This observation is some 2 decades old, and its implications for the assessment of QTc changes by drugs changing heart rate are well understood . The so‐called individual heart corrections (providing the QTcI intervals) that reflect the subject‐specific QT/RR relationship are presently used in a number of studies …”

Cardiovascular Safety Considerations in the Treatment of Neurogenic Orthostatic Hypotension

“…72 Little to no effect of droxidopa on heart rate has been observed in patients with nOH or healthy individuals. 70,73 In healthy individuals, meaningful changes in QTc interval were not observed with therapeutic or supra-therapeutic doses of droxidopa, 73 and it is likely droxidopa would have less effect in nOH populations because of centralized autonomic nervous system denervation. 74 Further study of droxidopa is required regarding use in patients with cardiovascular disease and effects on myocardial volume oxygen and contractility.…”

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

“…Reviews published in 2005 by Strnadova and 2011 by Satin and colleagues capture respective “snapshots in time” in this field. References to examples of individual TQT studies and related considerations are provided …”

“…References to examples of individual TQT studies and related considerations are provided. [35][36][37][38][39][40][41][42]…”