Examining the Clinical Utility of Lacosamide
ABSTRACT Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool.
To provide insight into the clinical utility of lacosamide by performing a priori-defined and post hoc analyses on a large, pooled patient population.
Pooled data from three randomized, double-blind, multicentre, placebo-controlled phase II/III trials.
Adult patients with partial-onset seizures with or without secondary generalization (N = 1294).
Four- to six-week titration followed by 12-week maintenance treatment with lacosamide (Vimpat®) 200, 400 or 600 mg/day or placebo.
A priori-defined primary efficacy variables for the pooled analysis were change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase; a priori-defined secondary efficacy variables were the proportion of patients achieving a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate), the proportion of Maintenance Phase completers remaining seizure free throughout the entire Maintenance Phase and the percentage of seizure-free days during the Maintenance Phase for patients entering the Maintenance Phase. The pooled analyses of the change in seizure frequency, and 50% and 75% responder rates were performed with an intent-to-treat (ITT) approach, including all patients receiving at least one dose of trial medication and having at least one post-baseline efficacy assessment. Similar analyses of the two primary efficacy variables and 75% responder rates were also performed using a modified ITT population (ITTm) that included ITT patients who entered the Maintenance Phase. Additional post hoc efficacy analyses were an evaluation of onset of efficacy and assessment of efficacy in patients grouped by prior surgical history and individual concomitant AED use. In addition, pharmacokinetic-pharmacodynamic modelling was performed, and safety data were assessed.
In this pooled analysis of 1294 difficult-to-treat patients, all three dosages of lacosamide (200, 400 and 600 mg/day) showed a significant improvement compared with placebo for median percent seizure reduction (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day), as well as for 50% responder rate (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day). Evaluation of 75% responder rate in the phase II/III pooled population showed that a significantly higher proportion of patients randomized to lacosamide 400 or 600 mg/day achieved a ≥75% reduction in seizure frequency compared with placebo (ITT and ITTm; p < 0.001); statistical significance was not observed for lacosamide 200 mg/day (ITT and ITTm). A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%). The mean change from baseline in the percentage of seizure-free days in patients entering the Maintenance Phase for the phase II/III pool was 8.0%, 11.6% and 14.7% with lacosamide 200 (p = 0.077), 400 (p < 0.001) and 600 (p < 0.001) mg/day groups, respectively, compared with 6.1% in the placebo group. The onset of efficacy relative to placebo was evident by the first week of treatment with lacosamide. Efficacy was similar in lacosamide-treated patients reporting prior surgical intervention for epilepsy compared to lacosamide-treated patients with no prior surgical intervention. Lacosamide showed a reduction in seizures, regardless of the concomitant AEDs used. The preferred pharmacokinetic-pharmacodynamic model (E(max)) supported the therapeutic dose range of lacosamide, and no additional safety concerns were identified in the phase II/III pooled analysis.
Results of these a priori-defined and post hoc pooled data analyses from phase II/III trials demonstrate that lacosamide effectively reduces seizures in patients at all three dosages evaluated with an early onset of efficacy, regardless of patient surgical history and concomitant AED regimen.
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ABSTRACT: Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug's efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such comparative trials are overall lacking for new AEDs, although some conclusions can be drawn from the available data. In the end, however, AED selection must be based on individual patient and drug characteristics.08/2011; 2(4):141-58. DOI:10.1177/2042098611411127
Article: Novel medications for epilepsy.[Show abstract] [Hide abstract]
ABSTRACT: Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmacoresistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization. Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults. Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.2-7.5 potassium channels. All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 8-20 hours for eslicarbazepine, 12-16 hours for lacosamide and 6-10 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin. The approved effective dose ranges are 200-400 mg/day in two divided doses for lacosamide, 800-1200 mg/day once daily for eslicarbazepine acetate, and 600-1200 mg/day in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50% reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 37-43% vs 13-20% for placebo; lacosamide: 38-41% vs 18-26% for placebo; retigabine: 33-44% vs 16-18% for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine. The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, their use is largely restricted to the adjunctive treatment of focal seizures, with or without secondary generalization, in adults with epilepsy who failed to achieve seizure freedom after having tried two or more first-line agents.Drugs 11/2011; 71(16):2151-78. DOI:10.2165/11594640-000000000-00000 · 4.13 Impact Factor
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ABSTRACT: Although many different medical and surgical treatment options for epilepsy exist, approximately 30% of epilepsy patients remain poorly controlled. For those patients who are refractory to medical treatment, epilepsy surgery often provides meaningful improvement. However, when surgical resection of epileptic foci cannot be offered or failed, combined administration of AEDs or the application of novel AEDs is the most appropriate therapeutic options. The most recent AEDs tend to offer new mechanisms of action and more favorable safety profiles than the first generation of AEDs. More recently, alternative options of thalamic or cortical stimulation emerged as potentiall effective treatment for epilepsy. The purpose of this article is to compare and review clinical information for the new and emerging medications such as lacosamide, eslicarbazepine acetate, ezogabine (retigabine), rufinamide, perampanel, as well as deep brain stimulation and responsive neurostimulation devices.12/2011; 1(2):35-46. DOI:10.14581/jer.11008