Abstracts

Rationale: The metabolites of eslicarbazepine acetate (ESL) are excreted in urine in the unchanged form or conjugated with glucuronic acid and their clearance has been shown to be dependent on renal function. Metformin is a commonly used antidiabetic; its elimination occurs mainly via the kidney and is affected by renal function. Therefore, an interaction study between ESL and metformin at the renal excretion level could be hypothesized. This study aimed to investigate whether multiple-dose administration of ESL affects the pharmacokinetics of metformin. Methods: This was a single centre, randomised, open-label, two-period crossover study in 20 healthy volunteers. The volunteers were administered a single 850 mg oral dose of metformin hydrochloride alone (Reference) and after pre-treatment with ESL 1200 mg once daily, for 6 days (Test). There was a washout of 2 weeks or more between periods. The potential drug-drug interaction was assessed using the bioequivalence approach. Test/Reference geometric mean ratios (GMR) and 90% confidence intervals (90% CI) were calculated for AUC0-∞, AUC0-12 and Cmax of metformin. Results: Mean±SEM plasma concentration-time profiles of metformin administered alone (Reference) or concomitantly with ESL 1200 mg (Test) are presented in Figure 1. Test/Reference metformin GMR (90% CI) was 0.95 (0.86, 1.05) for AUC0-∞, 0.95 (0.88, 1.06) for AUC0-12, and 0.88 (0.77, 1.00) for Cmax. The extent of exposure to metformin, as reflected by AUC0-12 and AUC0-∞, allows the claim of bioequivalence since the 90% CI of the GMR fall within the pre-specified bioequivalence acceptance interval (0.80, 1.25). Formal bioequivalence could not be demonstrated for metformin Cmax, but the bioinequivalence was due to an acute gastroenteritis in a subject during the ESL 1200 mg plus metformin period, which significantly compromised the oral absorption of metformin. Conclusions: Once-daily administration of ESL 1200 mg has no relevant effect on the systemic exposure to metformin pharmacokinetics in healthy subjects and no adjustment in the dose of metformin appears to be necessary when it is co-administered with ESL. Support: BIAL - Portela & Co, SA.