A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects.
OBJECTIVE
This randomized, double-blind, placebo- and positive-controlled 4-way crossover study evaluated the effects of tapentadol immediate release (IR) on the QT/QTc interval.


METHODS
Healthy subjects received tapentadol IR 100 mg or 150 mg, or placebo, every 6 h on Days 1 and 2, with a >= 7-day washout between treatments. Moxifloxacin 400 mg was the positive control. Serial triplicate 12-lead electrocardiograms (ECGs) were performed; the Fridericia correction (QTcF) was the primary correction method. Serial blood sampling was performed for pharmacokinetic analyses.


RESULTS
Of the 75 subjects who were randomized, 68 received at least 1 dose of study medication, and 59 completed the study. Upper limits of the 90% confidence intervals (CIs) for the difference in mean DeltaQTcF between tapentadol IR 100 or 150 mg and placebo were < 10 ms (non-inferiority criterion) for all time points. The lower limit of the 90% CI for mean DeltaQTcF between moxifloxacin and placebo exceeded 5 ms from 1 to 6 h after dosing, establishing assay sensitivity. No subject had a postdose QTc interval > 480 ms, change from baseline > 60 ms, or clinically relevant change in heart rate or other ECG variables. Steady-state concentrations were reached within 18 to 24 h. Common adverse events were vertigo (central nervous system (CNS) origin), headache, somnolence, nausea, vomiting, and feeling drunk.


CONCLUSIONS
Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval.
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Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA. coh2@its.jnj.com
Rengelshausen
J
J
Mangold
B
B
Etropolski
M
M
Rauschkolb
C
C
Wang
S S
SS
Upmalis
D
D
Häufel
T
T
D000328:Adult; D000368:Aged; D000700:Analgesics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010636:Phenols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000077432:Tapentadol
D000700:Analgesics; D010636:Phenols; D017450:Receptors, Opioid, mu; D000077432:Tapentadol