Mutual interaction between remacemide hydrochloride and phenytoin

A randomised, double-blind, placebo-controlled crossover study of add-on remacemide hydrochloride was carried out in epilepsy patients being treated with phenytoin (PHT) monotherapy. Eleven patients were recruited, ten of whom completed the study. Plasma concentration profiles of PHT, remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single and multiple dosing with remacemide hydrochloride. Following 14 days' treatment with remacemide hydrochloride 300 mg twice daily, the mean AUC of PHT was increased by 11.5% (P = 0.33), C-max by 13.7% (P = 0.32) and C-min by 22.2% (P = 0.12) over placebo. There was an increase in trough concentrations of PHT averaging 20% during active treatment compared with placebo (P = 0.01). No symptoms of PHT toxicity were reported by any patient. There was no evidence of autoinduction of remacemide metabolism. However, average concentrations of remacemide and its active metabolite in PHT-treated patients were around 40 and 30% lower, respectively than in healthy volunteers previously receiving the same dose of remacemide hydrochloride. Thus, remacemide hydrochloride has a small inhibitory effect on PHT metabolism, which itself induces that of remacemide and its active metabolite. This mutual interaction is predictable and modest and should not present a barrier to their clinical use in combination. (C) 1997 Elsevier Science B.V.