Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a novel once-daily (QD) anticonvulsant, extensively converted to eslicarbazepine after oral administration. Eslicarbazepine is a voltage-gated sodium- and calcium-channel blocking agent. Some patients with refractory partial onset seizures may require administration of crushed tablets, thus it is important to understand the pharmacokinetic (PK) characteristics of ESL administered as crushed tablet relative to intact tablet. This study compared the relative bioavailability and bioequivalence of a crushed or intact tablet administered orally to healthy volunteers. Methods: Healthy male and female volunteers age 18 to 50 years were enrolled in a single dose (ESL 800 mg) open label, randomized, two-period, cross-over study, with a 5-day washout period between treatments. Following an overnight fast, subjects were randomized to two different sequences of intact or crushed tablet of ESL 800 mg. Crushed tablets were sprinkled on 4oz (113 g) of applesauce followed by 240 mL water. Blood samples were analyzed for measurements of ESL and its main metabolites; PK parameters were derived for eslicarbazepine. Bioequivalence was determined if the eslicarbazepine Least Squares (LS) Mean ratios and 90% Confidence Interval (CI) for AUC_0-∞ and C_max fell within 80%-125%. Results: A total of 27 subjects completed both arms of the study. Mean age was 27 years (SD = ± 8) with 75% males, and 68% Caucasian. The PK parameters for eslicarbazepine after oral administration of crushed or intact tablets are shown in Table 1. The LS Mean ratios and 90% CI for eslicarbazepine comparing the crushed tablet to the intact tablet were: C_max (ng/mL) 1.030 (0.971, 1.090) and AUC_0-∞ (ng*h/mL) 0.967 (0.944, 0.992). Adverse events reported by >1 subject included fatigue (n=3; 11%), excoriation (n=2; 7%), headache (n=3; 11%), and somnolence (n=2; 7%). Conclusions: In this study, administration of ESL 800 mg to healthy volunteers as a crushed or intact tablet was shown to be bioequivalent. The eslicarbazepine median T_max and mean T_1/2 were similar whether the ESL tablet was crushed or taken intact. This study showed that the pharmacokinetic profile of ESL is not significantly altered by crushing, indicating that ESL tablets can be administered crushed or intact.