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.     

Efficacy and Safety of Carisbamate in Patients with Diabetic Neuropathy or Postherpetic Neuralgia: Results from 3 Randomized,Double‐Blind Placebo‐Controlled Trials

The results of 3 proof‐of‐concept studies to evaluate carisbamate's efficacy and safety in treating neuropathic pain are presented. In studies 1 (postherpetic neuralgia, n = 91) and 2 (diabetic neuropathy, n = 137), patients received carisbamate 400 mg/day or placebo for 4 weeks and then crossed over to the other treatment for 4 weeks. In study 3 (diabetic neuropathy, higher carisbamate doses), patients (n = 386) were randomized (1:1:1:1) to receive either carisbamate 800 mg/day, 1200 mg/day, pregabalin 300 mg/day or placebo for 15 weeks. Primary efficacy end point was the mean of the last 7 average daily pain scores obtained on days the study drug was taken, for all 3 studies. Least square mean (95% CI) differences between carisbamate and placebo groups on the primary end point were as follows: study 1: ?0.512 (?1.32, 0.29) carisbamate 400 mg/day; study 2: ?0.307 (?0.94, 0.33) carisbamate 400 mg/day; and study 3: ?0.51 (?1.10, 0.08), carisbamate 800 mg/day; ?0.55 (?1.13, 0.04), carisbamate 1200 mg/day; and ?0.43 (?1.01, 0.15), pregabalin 300 mg/day. Neither carisbamate (all 3 studies) nor pregabalin (study 3) significantly differed from placebo, although multiple secondary end points showed significant improvement in efficacy with carisbamate in studies 1 and 2. Dizziness was the only treatment‐emergent adverse event occurring at ≥10% difference in carisbamate groups versus placebo (study 1: 12% vs. 1%; study 3: 14% vs. 4%; study 2: 1% vs. 2%). Carisbamate, although well tolerated, did not demonstrate efficacy in neuropathic pain across these studies, nor did the active comparator pregabalin (study 3).     

Evaluation of Carisbamate for the Treatment of Migraine in a Randomized, Double-Blind Trial

Objective.— This study explored the dose‐response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine. Background.— Carisbamate ([S]‐2‐O‐carbamoyl‐1‐o‐chlorophenyl‐ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis. Design/Methods.— This was a double‐blind, placebo‐controlled trial, approximately 22‐week duration. The primary efficacy variable was the percent reduction from baseline through the double‐blind phase in average monthly migraine frequency using a 48‐hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4‐week baseline period, which was followed by a 2‐week titration period, a 12‐week maintenance period, a 1‐week medication reduction period, and a 3‐week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3‐month history of 3‐12 migraine attacks per month. Results.— Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P ≥ .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (?250%, 100%) for placebo; 33% (?210%, 100%; P = .7) CRS 100 mg/day; 27% (?100%, 100%; P = .8) CRS 300 mg/day; and 35% (?87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24‐hour rule, and percent reduction in average monthly migraine days) were consistent (P ≥ .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate‐treated patients (13% each). The most common (occurring in ≥5% of patients) treatment‐emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related. Conclusions.— Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well‐controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.     

Carisbamate in essential tremor: Brief report of a proof of concept study

The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double‐blind, cross‐over, placebo‐controlled study of essential tremor. Sixty‐two patients (intent‐to‐treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21‐day treatment periods. The Fahn‐Tolosa‐Marín Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo. © 2010 Movement Disorder Society     

Investigation of the effects of the novel anticonvulsant compound carisbamate (RWJ-333369) on rat piriform cortical neurones in vitro

Background and purpose:

Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices.

Experimental approach:

Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings.

Key results:

Carisbamate (50–400 µmol·L⁻¹) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na⁺ channel block; 150–400 µmol·L⁻¹ carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl⁻ loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 µmol·L⁻¹) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl⁻ conductance. Lidocaine (40–320 µmol·L⁻¹) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 µmol·L⁻¹) had no effect on spontaneous GABA_A miniature inhibitory postsynaptic currents and at lower concentrations (50–200 µmol·L⁻¹) inhibited Mg²⁺-free or 4-aminopyridine-induced seizure-like discharges.

Conclusions and implications:

Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na⁺ channels and increased Cl⁻ conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals.