Abstracts

Rationale: Previous analyses of sudden unexpected death in epilepsy (SUDEP) cases have failed to indicate an increased incidence of SUDEP with exposure to Lamotrigine (LTG). However, LTG has been reported to inhibit hERG-channel tail-current in a concentration-dependent manner with nominal IC20 and IC50 values of 21 and 229µM respectively [Danielson et al 2005] leading to speculation that some cases of SUDEP with LTG use could be due to QT interval prolongation and cardiac arrhythmia [Aurlien et al 2007]. Although pre-clinical, clinical and post-marketing data suggest no evidence of an association between QT prolongation and associated cardiac arrhythmias and LTG treatment, this study was conducted to characterise the effects of LTG on QT.Methods: Healthy volunteers aged between 18 and 55 years received a single oral dose of 400mg moxifloxacin or placebo in a randomised, single blind, crossover design, with a week washout between doses. After a further washout period, they were then randomised to receive either a dose-escalating regimen of LTG (N=76) to 400 mg qd over a 77-day period, or matched placebo (N=76), in a double blind, parallel group design. Blood samples were taken for assay of moxifloxacin and LTG. Digital 12-lead ECGs were recorded in triplicate at each time point over 24h after the moxifloxacin /placebo dose and for 12h after the LTG/placebo dose on days 42 (50mg bid), 63 (150mg bid) and 77 (200mg bid). QT intervals were measured manually by a central reader and corrected using Fridericia’s formula. QTcF was analysed using separate, repeated-measures analysis of covariance models. The point estimates and corresponding 90% confidence intervals were calculated for the difference between LTG and corresponding placebo on days 42, 63 and 77 at all time points using the appropriate error term. The relationship between individual QT values and their respective individual moxifloxacin or lamotrigine concentrations were explored using Population PK/PD modelling. Results: No prolongation of QTcF was observed on any dose of LTG. Moxifloxacin produced a robust prolongation of QTcF. A small reduction in QTcF and a small increase in heart rate were observed on LTG compared with placebo. No effect of LTG on QRS duration or blood pressure was observed. No outliers were observed in the LTG group, in terms of subjects with QTcF >450msec, or with an increase from baseline of >60msec [Table]. The PK/PD model indicated that there were statistically significant decreases for LTG and increases for moxifloxacin in QTcF intervals over the concentration ranges studied. Conclusions: The results of this study support the absence of significant prolongation of QT with lamotrigine at monotherapy doses up to 400 mg qd. These data concur with the extensive clinical and post-marketing experience, that it is unlikely that there is an association between QT interval prolongation, or associated cardiac arrhythmias, with lamotrigine treatment.