Epilrpsia, zyxwvutsrqponmlk 37( zyxwvutsrqponm I1):1100-1106, zyxwvutsrqponm 1996 Lippincott-Raven Publishers, Philadelphia zyxwvutsrq 0 International League Against Epilepsy Mutual Interaction Between Remacemide Hydrochloride and Carbamazepine: Two Drugs with Active Metabolites John Paul Leach, Jackie Blacklaw, *Virginia Jamieson, "Tracey Jones, ?Alan Richens, and Martin J. Brodie zyxwv Epilepsy Research Unit, University Department zyxwvut of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; *Astra Charnwood, Laughborough, England; and f University of Wales College of Medicine, Cardig Wales, U.K. Summary: Purpose: We wished to determine mutual inter- action of two drugs with active metabolism: remacemide, hy- drochloride and carbamazepine (CBZ). Methods: A randomized, double-blind, placebo-controlled cross-over study of add-on remacemide hydrochloride was per- formed 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 , was increased by 27% (p = 0.07), and Cmin 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 unaf- fected. No symptoms of CBZ toxicity were reported. There was no evidence of autoinduction of remacemide metabolism. How- ever, in CBZ-treated patients, the AUC of remacemide and its active metabolite was 60 and 30%, respectively, of values ob- served in healthy volunteers treated previously with the same dose. Conclusions: Remacemide hydrochloride inhibits CBZ me- tabolism, which itself induces that of remacemide hydrochlo- ride 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 combi- nation. Key Words: zyxw Epilepsy-Carbamazepine-Remacemide hydrochloride-Drug interaction. Remacemide hydrochloride (2-amino-N-[ 1 -methyl- 1,2-diphenylethyl]-acetamide monohydrochloride) is a novel anticonvulsant (1). Metabolism in humans in- volves production of an active desglycinyl metabolite ARL12495XX (2), which has a longer elimination half- life (tYz: 11-19 vs. 3-4 h) than the parent compound (3). Both compounds are inhibitors of sodium channels and, in addition, the metabolite is a low-affinity noncompeti- tive N-methyl-D-aspartate (NMDA) receptor antagonist (1,4). As well as being an anticonvulsant (3, rema- cemide hydrochloride could be effective in preventing cell damage (6) in the course of ischemic injury (7) and in Parkinson's disease, in which it has been shown to alleviate symptoms in rodents and primates in combina- tion with subtherapeutic doses of levodopa (8). Carbamazepine (CBZ) is a first-line antiepileptic drug (AED) (9). Its use is complicated by variable autoinduc- tion of metabolism (10) and a propensity for pharmaco- kinetic drug interactions (1 1). Hepatic metabolism of CBZ in humans produces an active 10,11 epoxide (CBZ- E) metabolite, which is believed to be responsible for some of its neurotoxic side effects (12). Metabolism of this compound is also affected by other AEDs (13). The predilection of the established AEDs to interact with other compounds and the need for novel agents to be used as adjuvant therapy require early assessment of po- tential pharmacokinetic interactions, which can obscure interpretation of trial results and influence dose selection (14). We conducted a pharmacokinetic interaction study with remacemide hydrochloride in patients receiving CBZ monotherapy, using a randomized, double-blind, placebo-controlled, cross-over design (15). PATIENTS AND METHODS Fourteen patients were recruited (Table I), each re- Accepted July zyxwvutsrqpon 15, 1996. ceiving a regimen of CBZ (Tegretol, Ciba) as the only least 3 months. All patients had at least two plasma mea- Address correspondence and reprint requests to Professor M. J. Brodie at Epilepsy Research Unit, Department of Medicine and Thera- AED therapy, the dose Of which had been for at peutics, Western Infirmary, Glasgow G1 l 6NT, Scotland. zyxwvutsr 1100