Effect of brivaracetam on cardiac repolarisation – a thorough QT study^*

ABSTRACT

Objectives: To assess the effect on cardiac repolarisation of the investigational synaptic vesicle protein 2A (SV2A) ligand brivaracetam.

Research design and methods: Subjects received double-blind, multiple bid doses of placebo (n = 53), brivaracetam 75 mg (n = 39) or brivaracetam 400 mg (n = 40), or open-label single-dose moxifloxacin 400 mg (positive control, n = 52). Continuous 12-lead ECG recordings were performed at baseline and after last dosing, using a Mortara Holter device. Plasma samples were obtained before and up to 12 h after last dosing for drug determination. Triplicate ECGs were extracted before each sample, and read centrally in a blinded manner. QT was corrected using a centre- and gender-specific correction (QTc_SS).

Main outcome measures: The primary endpoint was the largest time-matched mean difference of QTc_SS change from baseline between drug and placebo (maximum ΔΔQTc_SS). The same approach was adopted using the Fridericia's correction (QTc_F). The relationships between ΔQTc_SS and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression.

Results: Mean maximum ΔΔQTc_SS for brivaracetam 75 and 400 mg bid, and moxifloxacin 400 mg was 0.2 ms, −1.1 ms and 12.4 ms, respectively. The one-sided 95% upper limit for 75 mg and 400 mg brivaracetam was 4.3 ms and 3.0 ms, respectively; the one-sided 95% lower limit for moxifloxacin was 8.6 ms. After brivaracetam no QTc_SS intervals >480 ms or changes from baseline of >60 ms were observed. ΔQTc_SS did not increase with plasma concentration of brivaracetam, whereas there was a statistically significant rise with increasing moxifloxacin concentrations.

Conclusions: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development.

Key words: :

• Brivaracetam
• Epilepsy
• Healthy subjects
• Moxifloxacin
• Thorough QT study

Acknowledgements

Declaration of interest: This study and analysis were funded by UCB Pharma SA. We declare that the study reported herein complied with the current laws of the country in which it was performed.

D.R. was an employee of the R&D Department at UCB Pharma SA at the time of the study. B.A., an employee of Biotrial, has received compensation for her work, but has no other financial arrangement with UCB Pharma. All remaining authors are permanent employees of the R&D Department at UCB Pharma SA.

The authors are grateful to Pierre Boulanger (Development Metabolism & Pharmacokinetics, UCB Pharma SA) and Rebecca Davis (Covance Laboratories, Harrogate, United Kingdom) for analytical support and Soumaya Bendahmane (employee of UCB Pharma SA at the time of the study) for operational support. The authors thank David Pickles of InforMed Direct, UK, for support with manuscript editing, which was funded by UCB Pharma SA.

Notes

* The results of this study have been presented as a poster at the 61st Annual Meeting of the American Epilepsy Society (Philadelphia, PA, USA; 30 November–4 December 2007)