Thorough QT/QTc study in patients with advanced Parkinson's disease: cardiac safety of rotigotine.
The potential effects of the dopamine agonist rotigotine on cardiac repolarization were studied in patients with Parkinson's disease, which affects electrocardiogram (ECG) quality. The parallel-group trial was double-blind and placebo- and positive (moxifloxacin 400 mg)-controlled. After two 24-h baseline ECGs, patients were randomized to rotigotine (n = 66) or placebo (n = 64). Twenty four-hour ECGs were recorded on days 14/15, 21/22, 28/29, 35/36, and 42/43 of a regimen involving weekly dose escalations of 4 mg/24 h (4 mg/24 h-24 mg/24 h). In 10-s ECGs (n = 357,948) selected from 24-h records, QT measurements were manually verified and individually rate-corrected (QTc). Assay sensitivity showed maximum mean 13.5 ms QTc prolongation after moxifloxacin with 95% confidence interval (CI) 11.8-15.2 ms. Rotigotine vs. placebo differences in time-matched changes from baseline (54 data points/24 h) showed mean effects close to zero with upper one-sided 95% CI <5 ms. Accurate, thorough QTc studies are possible even in patients with diseases that profoundly affect ECG quality. Rotigotine in supra- and therapeutic doses was shown not to affect cardiac repolarization.
Malik
M
M
St. Paul's Cardiac Electrophysiology, London, England. marek.malik@btinternet.com
Andreas
J-O
JO
Hnatkova
K
K
Hoeckendorff
J
J
Cawello
W
W
Middle
M
M
Horstmann
R
R
Braun
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010300:Parkinson Disease / Q000188:drug therapy*; D011804:Quinolines / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D013876:Thiophenes / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*
D000890:Anti-Infective Agents; D001372:Aza Compounds; D018491:Dopamine Agonists; D024841:Fluoroquinolones; D011804:Quinolines; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D000077266:Moxifloxacin