Abstracts

Rationale: The primary treatment objectives for patients with epilepsy (PWE) are maintenance of relatively stable and effective AED levels and prevention of breakthrough seizures. Compliance with the prescribed dosage regimen is essential for the maintenance of therapeutic blood levels. A formulation that can be dosed once-daily is considered clinically advantageous and may improve compliance. We report results from a multicenter trial with a new once-daily extended-release formulation of lamotrigine (LTG-XR). LTG-XR is an enteric-coated, slow-release formulation suitable for once-daily dosing in epilepsy regardless of concomitant AED. The objective of the trial was to compare the pharmacokinetics (PK) of immediate-release lamotrigine (LTG-IR) given twice-daily to LTG-XR in PWE.Methods: This was an open-label, conversion study consisting of a 2-week LTG-IR Baseline Phase, a 2-week LTG-XR Treatment Phase and a 1-week LTG-IR Follow-Up Phase. Forty-four (44) PWE (≥13 years of age) were grouped as neutral (N=15), induced (N=15) and inhibited (N=14) based on the effects of their concomitant AEDs on LTG PK. Outcomes included LTG PK upon conversion, seizure frequency during each treatment phase and subjects’ preference at the end of study. Results: The rate of absorption of LTG was slower with LTG-XR vs LTG IR. The median postdose Tmax with LTG-IR was 1-1.5 hours; with LTG-XR the postdose Tmax was increased to 4-6 hours for induced group, 6-10 hours for neutral group, 9-11 hours for inhibited group. While the steady-state dose-normalized trough concentrations of LTG XR were similar to those observed for LTG-IR, the steady-state dose-normalized Cmax values after administration of LTG-XR were ~30% lower in the induced group and ~10% lower in the neutral and inhibited groups compared to LTG-IR; the geometric least squares mean ratio (90% CI) were 0.71 (0.613, 0.823) (induced group), 0.89 (0.775, 1.026) (neutral group), 0.88 (0.750, 1.030) (inhibited). This reduction in the LTG Cmax with LTG-XR resulted in a decrease in the peak to trough fluctuation in serum LTG concentrations. The fluctuation index was reduced by 17% in the induced group, 37% in the neutral group, 34% in the inhibited group. The dose-normalized AUC(0-24) values with LTG-XR were on average 21% lower than with LTG-IR in the induced group, but in the neutral and inhibited groups these values were comparable between LTG-XR and LTG-IR; the geometric least squares mean ratio (90% CI) were 0.79 (0.688, 0.899) (induced group), 1.00 (0.882, 1.140) (neutral group), 0.88 (0.750, 1.030) (inhibited group). There was no change in the median weekly seizure frequency. At the end of the LTG-XR Phase, 24 (24/35, 69%) subjects indicated that they preferred the once-a-day regimen and 6 (6/35, 17%) subjects expressed no preference. Conclusions: Conversion from twice-daily LTG-IR to once-daily LTG-XR can be done on a milligram to milligram basis with maintenance of steady-state trough LTG concentrations regardless of concomitant AEDs.