Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily, oral antiepileptic drug (AED) for partial-onset (focal) seizures. In Phase III clinical trials of adjunctive ESL and ESL monotherapy, levels of free thyroxine (FT4) and free triiodothyronine (FT3) were lower in patients taking ESL versus placebo, when measured using the automated kit (AK) assay. It is possible that the metabolites of ESL may disrupt protein binding in serum samples (as has been previously demonstrated with phenytoin and carbamazepine), resulting in lower measurements of free thyroid hormones by the AK assay, compared with samples not containing ESL metabolites. The current study investigates whether ESL metabolites interfere with the measurement of thyroid hormones by the AK assay, to assess whether this technique is suitable for the measurement of thyroid hormone levels in patients taking ESL. Methods: Study 093-451 was comprised of two parts. Part 1 measured thyroid hormone levels in serum samples from patients who had received ESL =1,200 mg per day for =6 weeks. Part 2 used serum samples from healthy volunteers (age/gender matched) who had not been exposed to ESL, which were spiked with different concentrations of ESL metabolites (low: 5.0 and 0.5 µg/mL eslicarbazepine and (R)-licarbazepine, respectively; medium: 12.5 and 1.25 µg/mL; high: 20.0 and 2.0 µg/mL). Both parts used the AK assay and optimized equilibrium dialysis (ED; a ‘gold standard’ physical separation technique) to measure serum levels of FT4 and FT3. Serum levels of thyroid stimulating hormone (TSH), total T4 (TT4), total T3 (TT3), and thyroxine binding globulin (TBG) were also measured. Data are reported as geometric means and ratios of geometric means. Results: The safety population was comprised of 62 patients (31 ESL-exposed patients, 31 healthy volunteers). Part 1: In ESL-exposed patient serum samples, FT4 measurements were similar between analytical techniques (AK, 12.29 pmol/L; ED, 11.74 pmol/L; ratio: 1.05 [90% CI: 0.98-1.12]). However, measurements of FT3 were slightly higher with the AK assay versus ED (AK, 4.20 pmol/L; ED, 3.65 pmol/L; ratio: 1.15 [90% CI: 1.09-1.22]). Part 2: In spiked serum samples from non-ESL exposed volunteers, there was a small ESL metabolite-dependent increase in FT4 and FT3 levels when measured using the AK assay (Table 1). Analyses of TSH, TT4, and TT3 levels suggested that ESL metabolites do not affect AK assay measurements (ratios between non-spiked and spiked samples [all concentrations] were ~1.0). When comparing results between the AK assay and ED, FT4 and FT3 measurements were slightly higher with the AK assay in both non-spiked and spiked serum samples (Table 2). Conclusions: There is no evidence to suggest that the presence of ESL metabolites leads to lower than normal thyroid hormone concentration measurements by the AK assay. Therefore, the lower thyroid hormone levels observed with ESL use (compared with placebo) in Phase III clinical trials were not due to assay interference. Funding: Study sponsored by Sunovion Pharmaceuticals Inc.