Third-generation antiepileptic drugs: mechanisms of action,pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.     

Emerging drugs for epilepsy

Epilepsy affects ≤ 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk individuals.     

Novel anticonvulsant medications in development

Epilepsy is currently the most prevalent neurological disorder worldwide. Pharmacological therapy remains the cornerstone of epilepsy treatment, however, refractory epilepsy is still a significant clinical problem despite the release of the second generation of anticonvulsants. Anticonvulsant treatment failures may result from lack of efficacy and presence of significant side effects. One rationale for incomplete effectiveness of the currently available anticonvulsants is that they were identified using the same classical models and therefore work largely by the same actions. These mechanisms fail to consider variations in the pathophysiological process that results in epilepsy, nor have they been shown to prevent the process of developing epilepsy (epileptogenesis). The next generation of anticonvulsants has taken into account the shortcomings of existing agents and attempted to improve on the currently available treatments using rationale drug design. This group of investigational anticonvulsants may be broadly classified as possessing one or more of the following: 1) increased tolerability through improvement in drug chemical structure or better delivery to the site of action, 2) new mechanisms (or combinations of mechanisms) of action, 3) improved pharmacokinetic properties. This article will discuss the next generation of anticonvulsants (carabersat, CGX-1007, fluorofelbamate, harkoseride, losigamone, pregabalin, retigabine, safinamide, SPD-421, talampanel, valrocemide) and the possible populations in which they would be clinically useful.