Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) for focal (partial-onset) seizures (FS). Liver and thyroid abnormalities were uncommon in clinical trials of ESL in adults with FS. Here, we evaluate the occurrence of hepatic and hypothyroidism-related events in clinical trials of adjunctive ESL for FS in children. Methods: Pooled safety data from subjects aged 4–17 years in Studies BIA-2093-208 and -305 were analyzed. Both trials were randomized, double-blind, placebo-controlled studies of adjunctive ESL in children with FS refractory to treatment with 1–2 AEDs. Study 208-Part 1 was a 12-week, Phase II study in subjects aged 6–16 years, with a target ESL dose of 30 mg/kg/day. Study 305-Part 1 was an 18-week, Phase III study in subjects aged 2–18 years, with a target ESL dose of 20 mg/kg/day. Periodic laboratory assessments of thyroid and hepatic parameters were conducted. Hepatic events: incidences of investigator-reported treatment-emergent adverse events (TEAEs) in the standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) of ‘drug-related hepatic disorders’ were evaluated, as well as laboratory assessments of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase (ALP). Hypothyroidism: incidences of investigator-reported TEAEs in the SMQ of ‘hypothyroidism’ that were fatal, serious, resulted in discontinuation, or required treatment were evaluated, as well as laboratory assessments of triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH). Results: The safety population (subjects aged 4–17 years who received =1 dose of study drug) included 362 subjects (ESL, n = 202; placebo, n = 160). Hepatic events: no subjects taking ESL met Hy’s law criteria (Hy’s Law suggests that hepatocellular injury sufficient to cause hyperbilirubinemia is an indicator that a drug may cause serious liver injury) or had persistent ALT/AST elevations. The only hepatic event (based on laboratory data) that occurred in the ESL group was ALP >1.5x the age-adjusted upper limit of normal (ULN) (ESL, 3.0%; placebo, 1.9%). One subject, randomized to placebo, experienced both ALT and AST >3x ULN. Hypothyroidism: the TEAE of ‘hypothyroidism’ was reported in two subjects taking ESL (1.0%) and one taking placebo (0.6%). There were no clinically significant changes between baseline and lowest/highest on-treatment values for free T3, free T4, or TSH; small changes were apparent, which were generally larger with ESL versus placebo. Conclusions: Hepatic events and hypothyroidism were rare during adjunctive treatment with ESL for FS in children aged 4–17 years. Funding: Studies sponsored by BIAL; analyses funded by Sunovion Pharmaceuticals Inc.