Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough QTc study.
BACKGROUND
Sugammadex reverses the effects of rocuronium- and vecuronium-induced neuromuscular blockade, which are achieved by encapsulation. It is known that some non-antiarrhythmic drugs have the potential to delay cardiac repolarization and it is therefore recommended that the effects of all new drugs on the QT interval are assessed.


OBJECTIVE
This thorough corrected QT (QTc) study evaluated the effect of sugammadex alone and in combination with rocuronium or vecuronium on the individually corrected QTc interval (QTcI).


METHODS
This was a randomized, double-blind, six-period crossover, placebo-controlled study, with an open-label active-controlled component (moxifloxacin). The study was designed according to International Conference on Harmonization (ICH) E14 guidelines. The study was conducted in a clinical research unit from November 2006 to April 2007. Healthy male and female subjects (n = 84) were enrolled in the study. Subjects were randomized to six treatment sequences comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control), sugammadex 4 mg/kg, sugammadex 32 mg/kg, sugammadex 32 mg/kg with rocuronium 1.2 mg/kg and sugammadex 32 mg/kg with vecuronium 0.1 mg/kg. Triplicate ECGs were recorded at 13 timepoints up to 23.5 hours after study drug administration and QT intervals were evaluated manually under blinded conditions. The primary outcome was the largest time-matched mean difference in QTcI change from baseline compared with placebo across the 13 timepoints up to 23.5 hours after study drug administration. Blood samples were also collected for pharmacokinetic analysis.


RESULTS
Of the 84 randomized healthy subjects, 80 completed the study. After moxifloxacin, QTcI prolongations were observed compared with placebo; the lower limit of the one-sided 95% confidence interval (CI) for the largest time-matched mean difference in QTcI change compared with placebo was 20.8 msec (90% CI 18.5, 23.1), thus exceeding the ICH E14 safety margin of 5 msec and demonstrating assay sensitivity. In contrast, the largest time-matched mean difference in QTcI (msec) from placebo with sugammadex treatments ranged from 2.1 (sugammadex 4 mg/kg alone) to 4.3 (sugammadex 32 mg/kg with vecuronium 0.1 mg/kg). For the largest time-matched mean difference in QTcI change compared with placebo the corresponding upper limit of the one-sided 95% CI was well below the 10 msec margin for both sugammadex doses. Telemetry results revealed that one subject experienced a non-sustained ventricular tachycardia 4 hours after sugammadex 32 mg/kg, which was self-terminating after 20 beats and considered unlikely to be drug related. Pharmacokinetic-QTc analysis showed a statistically significant (p < 0.01) relationship between sugammadex plasma concentration and QTcI; however, at mean maximum plasma concentrations of the therapeutic and supra-therapeutic sugammadex dose, the predicted one-sided upper 95% CI for the largest time-matched QTcI difference from placebo was below 10 msec. Rocuronium or vecuronium co-administration did not affect the relationship between sugammadex concentrations and QTc.


CONCLUSIONS
Based on the results of this study of healthy subjects, it can be concluded that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc prolongation.
de Kam
Pieter-Jan
PJ
Early Stage Development, MSD, Oss, the Netherlands. pieter-jan.dekam@merck.com
van Kuijk
Jacqueline
J
Prohn
Marita
M
Thomsen
Torben
T
Peeters
Pierre
P
D000293:Adolescent; D000328:Adult; D000732:Androstanols / Q000008:administration & dosage* / Q000009:adverse effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001372:Aza Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D003473:Neuromuscular Nondepolarizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D000077123:Rocuronium; D000077122:Sugammadex; D013997:Time Factors; D014673:Vecuronium Bromide / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult; D047408:gamma-Cyclodextrins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000732:Androstanols; D001372:Aza Compounds; D024841:Fluoroquinolones; D003473:Neuromuscular Nondepolarizing Agents; D011804:Quinolines; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D014673:Vecuronium Bromide; D000077266:Moxifloxacin; D000077123:Rocuronium