Thorough QT study with recommended and supratherapeutic doses of tolterodine.
The objective of our study was to determine the QTc effects of tolterodine. A crossover-design thorough QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo was performed. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on days 1-4; time-matched baseline ECGs were taken on day 0. Mean placebo-subtracted change from baseline Fridericia-corrected QT (QTcF) during peak drug exposure on day 4 was the primary end point. Mean QTcF prolongation of moxifloxacin was 8.9 ms (machine-read) and 19.3 ms (manual-read). At recommended and supratherapeutic tolterodine doses, mean QTcF prolongation was 1.2 and 5.6 ms (machine-read), respectively, and 5.0 and 11.8 ms (manual-read), respectively. The QTc effect of tolterodine was lower than moxifloxacin. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline. In conclusion, tolterodine does not have a clinically significant effect on QT interval.
Malhotra
B K
BK
Pfizer Inc., New York, New York, USA. bimal.k.malhotra@pfizer.com
Glue
P
P
Sweeney
K
K
Anziano
R
R
Mancuso
J
J
Wicker
P
P
D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D001372:Aza Compounds / Q000493:pharmacokinetics; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D003408:Cresols / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D000077266:Moxifloxacin; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D010665:Phenylpropanolamine / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000493:pharmacokinetics; D000068737:Tolterodine Tartrate
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D001559:Benzhydryl Compounds; D003408:Cresols; D024841:Fluoroquinolones; D018727:Muscarinic Antagonists; D011804:Quinolines; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D019389:Cytochrome P-450 CYP2D6; D000077266:Moxifloxacin