Abstracts

Rationale: To assess the dose proportionality of the new once daily extended-release formulation of levetiracetam (LEV XR) 500 mg when taken as a single dose of two (1000 mg), four (2000 mg) or six (3000 mg) tablets. Methods: 24 healthy subjects (12 male /12 female), aged 22-52 years, were randomized in this open-label, 3-way cross-over study. Subjects received a single dose of 1000 mg, 2000 mg or 3000 mg LEV XR at each of three treatment periods under fasting conditions. Plasma LEV concentrations were determined serially until 48 h post-dose using a validated Liquid Chromatography-ElectroSpray Ionization/tandem Mass Spectrometry method and standard non-compartmental pharmacokinetic parameters were computed. Dose-proportionality of C_max, AUC(0-t) and AUC was assessed by linear regression between the log-transformed parameter and the log-transformed dose (power model). Dose proportionality was concluded if the 90% confidence interval (CI) for the slope was entirely included within the predefined acceptance range (0.797, 1.203). Dose independence of plasma half-life (t_1/2), apparent clearance (CL/F), and apparent volume of distribution (V_z/F) was evaluated using the same power model. Results: No absorption lag-time was apparent in any subject. The median time to maximum concentration (t_max) was 4.5h, 5h and 4.5 h and the mean maximum concentration (C_max) was 16, 32, and 46 μg/mL for 1000, 2000, and 3000 mg levetiracetam XR respectively. The corresponding mean AUCs were 285, 570, and 855 μg*h/mL. All doses resulted in a similar t_1/2 (around 7 h), CL/F (58 mL/min), and V_z/F (37 L). The rate (C_max; 90% CI: 0.907; 0.999) and the extent of absorption (AUC(0-t) and AUC; 90% CI:0.973;1.02) were found to be dose-proportional, while t_1/2, CL/F and V_z/F were dose-independent. The tolerability of each dose of LEV XR was good. No clinically relevant changes over time in vital signs, physical examination, and electrocardiogram data were noted. Conclusions: The pharmacokinetics of levetiracetam extended-release 500 mg tablet is dose-proportional in the range of 1000 to 3000 mg per intake. Study sponsored by UCB.