Fluorofelbamate.

Abstract

The incidence of refractory seizures has remained at 30-40%, even with the approval of nine new anticonvulsants over the past 12 years. In attempts to reduce seizure frequency and severity, physicians routinely resort to combining two or more anticonvulsants, ideally with different mechanisms of action. These combinatorial therapies are difficult to administer for both patient and caregiver and often result in tolerability issues. Hence, a broad spectrum anticonvulsant, with multiple mechanisms of action, that is well tolerated, would provide physicians with an important option in their armamentarium to control seizures. Felbamate initially fit this profile and was demonstrated to effectively control both partial and generalized seizures in clinical studies supporting registration. Unfortunately, unanticipated idiosyncratic toxicity was observed after approval and the drug is now relegated to second or third line therapy, depending on patient history and seizure type. Epileptologists still prescribe this drug for refractory seizures, and a recent communication indicates that 35,000 to 46,000 new patients have tried Felbatol (MedPointe Pharmaceuticals, Somerset, NJ) since 1995. The continued utilization of Felbatol, in light of its risk:benefit issues, highlights the need for new efficacious therapeutic options. Fluorofelbamate (MedPointe Pharmaceuticals), a phase I drug candidate, was designed to retain the broad spectrum multimechanistic activity of felbamate, with a modified metabolism that has demonstrated, in vitro, to avoid the production of the reactive metabolite believed to cause the idiosyncratic toxicity. This drug candidate is one of several carbamates either in development or currently on the market for treatment of seizures and other CNS disorders.