Abstracts

Rationale: To assess a possible threshold pharmacological effect of brivaracetam (BRV) on cardiac repolarisation, as detected by QT interval prolongation in a thorough QT study.Methods: Double-blind, 7 day multiple BID dosing of placebo (n=52), or 75 mg BRV (therapeutic dose, n=39), or 400 mg BRV (supra-therapeutic dose, n=39) and open-label single oral dose of 400 mg moxifloxacin (MOX; positive control, n=52) were randomly administered in 4 parallel groups of healthy male and female subjects. Continuous 12-lead ECGs were recorded during 12 h at baseline (Day -1) and following the last dose, using calibrated Mortara Holter devices. Plasma samples were obtained before and 0.5, 1, 1.5, 2, 4, 6, 9 and 12 h after the last dose for drug determination. Triplicate ECGs were extracted before each blood sampling and read centrally in a blinded manner. QT intervals were corrected for heart rate using a center- and gender-specific correction (QT_cSS). The primary endpoint was the largest time-matched mean difference of QT_cSS) change from baseline between drug and placebo (max.ΔΔQT_cSS).Results: The mean max.ΔΔQT_cSS) for 75 mg BRV BID, 400 mg BRV BID and 400 mg MOX single dose was +0.2 ms, -1.1 ms and +12.4 ms, respectively. The one-sided 95% upper limit for 75 mg and 400 mg BRV was +4.3 ms and +3.0 ms, respectively; the one-sided 95% lower limit for MOX was +8.6 ms. No QT_cSS) interval >480 ms or change from baseline >60 ms was observed on BRV. No particular safety concern was observed during the study. There was no increase of ΔQT_cSS) with increasing plasma concentrations of BRV or its metabolites. In contrast, ΔQT_cSS) increased significantly with increasing moxifloxacin plasma concentrations.Conclusions: This thorough QT study is valid in terms of assay sensitivity. The results demonstrate the absence of effects of BRV on cardiac repolarisation. UCB Pharma funded.