Abstracts

Rationale: Levetiracetam extended-release tablets (LEV XR; Keppra XR ) qd are indicated by the FDA for adjunctive treatment of partial onset seizures in patients ?16 years old with epilepsy. Pharmacokinetic studies in healthy subjects ?18 years old have shown LEV XR (1000 mg qd) to be bioequivalent to LEV immediate release tablets (LEV IR; 500 mg bid).¹ This study evaluated the pharmacokinetics, safety and tolerability of LEV XR (1000-3000 mg/day) as adjunctive therapy in children (12-16 y) and adults (18-55 y) with epilepsy. Methods: This multicenter, open-label, two-arm study enrolled patients with localization-related or generalized epilepsy on 1-3 AEDs. Patients on stable dose of LEV IR had a mg-to-mg conversion into total daily dose of LEV XR (Keppra XR tablets, 500 mg and 750 mg) administered each morning over 4 to 7 days. For patients not taking LEV IR, LEV XR was administered as 1000 mg/day qd. LEV plasma concentrations were determined at pre-dose, 1, 2.5, 4, 6, and 10h after LEV XR administration on last dosing day using a validated HPLC/MSMS method. Pre-dose concentration was used as 24h concentration. Steady-state C_max and AUC_24h were obtained by non-compartmental methods, adjusted to a dose of 1000 mg/day (C_max,D and AUC_24h,D and normalized per kg bodyweight (C_max,DW and AUC_24h,DW). Children and adult values were compared statistically and 90% confidence intervals (CI) on geometric mean ratio were derived. Tolerability and safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests, ECGs, vital signs, physical and neurological examinations, and concomitant AED concentrations. Results: Twelve children (6M/6F; mean [range] age 14.9 y [13-16]) and 13 adults (5M/8F; 41.8 y [24-52]) were enrolled. Nine children and all adults were diagnosed with localization-related epilepsy. Children were most frequently on one concomitant AED. Three children and 11 adults converted their LEV IR treatment to LEV XR, the others initiated LEV XR. In both children and adults, median time to peak LEV XR plasma concentration was 6h (Figure 1). Mean C_max,D were 17.3 and 14.9 ?g/mL for children and adults. Corresponding mean AUC_24h,D were 265 and 236 ?g*h/mL. Variability on mean AUC_24h and C_max were similar between children and adults (Table 1). Ratios of AUC_24h,DW and C_max,DW between children and adults were close to 1 and their 90% CIs were within the 0.80-1.25 limits (AUC_24h,DW ratio:0.99; 90% CI:0.81-1.21). In both groups, 25% of the patients reported TEAEs, the most frequent were somnolence, nausea and vomiting (each in 2 [8%] patients). Drug-related TEAEs were reported by 16% of patients. Except one, severe vomiting, all drug-related TEAEs were mild; all TEAEs but one (pruritus) resolved at the end of trial. Tolerability was good for both patients converted from LEV IR to LEV XR and those initiated LEV XR. Conclusions: In children (13-16 years) and adults with epilepsy, LEV XR qd showed comparable steady-state pharmacokinetics and was well tolerated. UCB-sponsored (NCT00961441) 1.Rouits et al., Epi. Res. 2009;84:224-231