Mutual interaction between remacemide hydrochloride and carbamazepine: Two drugs with active metabolites

Purpose: We wished to determine mutual interaction of two drugs with active metabolism: remacemide, hydrochloride and carbamazepine (CBZ). Methods: A randomized, double-blind, placebo-controlled cross-overstudy of add-on remacemide hydrochloride was performed in 10 of 14 recruited patients being treated with CBZ monotherapy. Forty-eight-hour concentration profiles of CBZ, its active epoxide metabolite (CBZ-E), remacemide, and its desglycinyl metabolite (ARL12495XX) were assayed after single and multiple dosing. Results: After patients were treated with 300 mg remacemide hydrochloride twice daily for 14 days, the mean area under the concentration-time curve (AUC) of CBZ was increased by 22% (p = 0.12), C-max was increased by 27% (p = 0.07), and C-min was increased by 22% (p = 0.29). Trough concentrations of CBZ were higher (p = 0.0037) during active treatment as compared with placebo treatment. CBZ-E levels were unaffected. No symptoms of CBZ toxicity were reported. There was no evidence of autoinduction of remacemide metabolism. However, in CBZ-treated patients, the AUC of remacemide and its active metabolite was 60 and 30%, respectively, of values observed in healthy volunteers treated previously with the same dose. Conclusions: Remacemide hydrochloride inhibits CBZ metabolism, which itself induces that of remacemide hydrochloride and its active metabolite. This mutual interaction between remacemide hydrochloride and CBZ is predictable and modest and should not present a barrier to their clinical use in combination.