Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.
OBJECTIVE
Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI).


METHODS
Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points.


RESULTS
A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec.


CONCLUSIONS
Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.
Clinical Pharmacology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ 07065-0900, USA. pieterjan.de.kam@merck.com
Pieter-Jan
PJ
de Kam
Jacqueline
J
van Kuijk
Jean
J
Smeets
Torben
T
Thomsen
Pierre
P
Peeters
D000293:Adolescent; D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009465:Neuromuscular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects*; D000077122:Sugammadex; D047408:gamma-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects*
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009465:Neuromuscular Agents; D011804:Quinolines; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077266:Moxifloxacin