Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson's disease: a thorough QT/QTc study.
OBJECTIVE
Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinson's disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated.


METHODS
This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity.


RESULTS
247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure.


CONCLUSIONS
This TQT study demonstrated a favorable cardiac safety profile of rasagiline.
Boaz
B
Mendzelevski
Craig R
CR
Sprenger
Ofer
O
Spiegelstein
Laura
L
Rabinovich-Guilatt
D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D010300:Parkinson Disease / Q000188:drug therapy*; D055815:Young Adult
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline