Abstracts

Rationale: A new dosage strength of extended-release (XR) levetiracetam (LEV) 750 mg tablet is under development to provide an additional dosing option. This study was conducted to compare the bioavailability of a single dose of 2x750 mg LEV XR tablets, with that of 3x500 mg LEV XR tablets, to assess the effect of food and to obtain safety data on LEV XR 750 mg. Methods: 24 healthy adult subjects (12 male / 12 female) were randomized in this open-label, 3-way cross-over study. A single dose of 3x500 mg LEV XR in fasted condition, 2x750 mg LEV XR in fasted or fed conditions was administered during one of the three treatment periods. Plasma LEV concentrations were determined serially up to 48 hours post-dose using a validated LC-ESI/MSMS method and standard pharmacokinetic parameters evaluated by non-compartmental analysis. Bioequivalence or lack of significant food effect was concluded if the 90% confidence intervals (CIs) of the pairwise adjusted geometric means ratios (2x750XR/3x500XR or fed/fasted) were entirely contained within 80-125% limits for C_max and AUC. Results: Under fasted conditions, the median time to peak plasma concentration was approximately 4-5 hours for both LEV XR-dose formulations. Mean peak LEV concentration was 24.3, 21.5 and 23.5 μg/mL for 3x500 mg LEV XR, 2x750 mg LEV XR under fasted conditions and 2x750 mg LEV XR under fed conditions, respectively. The mean corresponding total exposure was 414, 415, and 388 μg*h/mL, respectively. All LEV XR formulations resulted in a similar t_1/2 (about 7.5 h), CL/F (about 60 mL/min), and Vz/F (about 40 L). Confidence intervals for comparisons of C_max, and AUC between 2x750mg LEV XR and 3x500 mg LEV XR were all within the bioequivalence limits: C_max (90% CI: 81-97%) and AUC (90%CI: 91-110%). When 2x750 mg LEV XR was taken with food, the time to peak was delayed by 2 hours relative to fasted intake, while C_max and AUC ratios remained within bioequivalence limits (90% CIs: 100-119% and 85-103%, respectively). About half of the subjects reported drug-related adverse events (AEs). The most frequently reported AEs were fatigue in 8 subjects (33%) and somnolence in 4 subjects (17%), which is consistent with LEV’s known tolerability profile. Except for one, which was moderate, all drug-related AEs were mild and all AEs resolved at the end of the study. Tolerability was good for all three treatments. Conclusions: In healthy male and female subjects, a single dose of 2x750 mg levetiracetam XR tablets was bioequivalent to that of 3x500 mg LEV XR tablets. Food intake did not significantly modify 2x750 mg LEV XR disposition. The new 750 mg LEV XR tablet was well tolerated. Study sponsored by UCB.