Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.
BACKGROUND
E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.


METHODS
Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).


RESULTS
In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.


CONCLUSIONS
The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.


BACKGROUND
EU Clinical Trials Register EudraCT 2010 020343 13.
Richmond Pharmacology Ltd., St George's University of London, Cranmer Terrace, London, United Kingdom; Cardiovascular and Cell Sciences Research Institute, St George's University of London, Cranmer Terrace, London, United Kingdom.
Jörg
J
Täubel
Statistik Georg Ferber GmbH, Cagliostrostrasse, Riehen, Switzerland.
Georg
G
Ferber
Richmond Pharmacology Ltd., St George's University of London, Cranmer Terrace, London, United Kingdom.
Ulrike
U
Lorch
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Duolao
D
Wang
Department of Clinical Investigation, ESTEVE Research & Development, Av. Mare de Déu de Montserrat, Barcelona, Spain.
Mariano
M
Sust
Cardiovascular and Cell Sciences Research Institute, St George's University of London, Cranmer Terrace, London, United Kingdom.
A John
AJ
Camm
D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D055815:Young Adult
C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine; D009025:Morpholines; D011720:Pyrazoles; D017480:Receptors, sigma