MUTUAL INTERACTION BETWEEN REMACEMIDE HYDROCHLORIDE AND CARBAMAZEPINE- 2 DRUGS WITH ACTIVE METABOLITES

Purpose: We wished to determine mutual interaction of two drugs with a ctive metabolism: remacemide, hydrochloride and carbamazepine (CBZ). M ethods: A randomized, double-blind, placebo-controlled cross-overstudy of add-on remacemide hydrochloride was performed in 10 of 14 recruite d patients being treated with CBZ monotherapy. Forty-eight-hour concen tration profiles of CBZ, its active epoxide metabolite (CBZ-E), remace mide, and its desglycinyl metabolite (ARL12495XX) were assayed after s ingle and multiple dosing. Results: After patients were treated with 3 00 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 increa sed 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. Howev er, in CBZ-treated patients, the AUC of remacemide and its active meta bolite was 60 and 30%, respectively, of values observed in healthy vol unteers treated previously with the same dose. Conclusions: Remacemide hydrochloride inhibits CBZ metabolism, which itself induces that of r emacemide hydrochloride and its active metabolite. This mutual interac tion between remacemide hydrochloride and CBZ is predictable and modes t and should not present a barrier to their clinical use in combinatio n.