Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r² = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.     

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.     

Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates

Introduction: There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox–Gastaut syndrome (LGS).

Areas covered: 1,4-disubstituted triazole ring formed by 1,3-dipolar cycloaddition reaction is an important structural motif widely used to construct diverse chemotypes in chemical, biological, and material fields. 1,2,3-triazole ring containing rufinamide, an antiepileptic drug developed by Novartis, is useful in combination with other antiepileptic medicaments for the treatment of childhood-onset epilepsy known as LGS. There are numerous synthetic methods used to construct the rufinamide through 1,3-dipolar cycloaddition. The application claims processes for the preparation of rufinamide and their intermediates. The synthetic strategy covered for the synthesis of rufinamide using activated acetylenic esters. The activation is done using N-hydroxy succinimide, N-hydroxyphthalimide, 1-hydroxy benzotriazole, and 4-nitro phenol.

Expert opinion: The manufacturing route appears to follow the regioselective Cu catalyzed cycloaddtion of 2,6-difluro benzyl azide with or without isolated activated acetylenic esters in three steps that provide a good lead for new synthetic strategy for the rufinamide synthesis.     

Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term,open‐label extension study

Kluger G, Glauser T, Krauss G, Seeruthun R, Perdomo C, Arroyo S. Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term, open‐label extension study.
Acta Neurol Scand: 122: 202–208.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective – This open‐label extension evaluated the long‐term efficacy and tolerability of rufinamide in patients with Lennox‐Gastaut syndrome (LGS) who had previously completed a 12‐week double‐blind study. Materials and methods – In total, 124 patients (aged 4–37 years), receiving 1–3 concomitant antiepileptic drugs, were treated with rufinamide ～25–60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. Results – Overall, patients were treated with rufinamide for a median (range) of 432 (10–1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had ≥50% reduction in total and tonic–atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). Conclusions – In this open‐label extension, rufinamide appeared to be an effective long‐term adjunctive therapy for the treatment of LGS‐associated seizures in children and young adults.     

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.     

Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: a meta-analysis of randomized,placebo-controlled trials

Aim

Epilepsy is a complex disease necessitating continuous development of new therapeutic strategies to encounter drug-resistant cases. Among new adjuvant antiepileptic drugs, rufinamide is structurally distinct from other antiepileptic drugs. It is used to treat partial-onset seizures and seizures associated with Lennox-Gastaut syndrome (LGS) in adult and children. To date, there has been no attempt to evaluate systematically the risks of adverse events with rufinamide.

Methods

We performed a quantitative risk analysis of central nervous system (CNS) adverse events of rufinamide from all randomized, double-blind, add-on, placebo-controlled trials. The meta-analysis was undertaken with fixed effects models.

Results

Of the 886 publications reviewed, 99 papers were retrieved and five articles met the inclusion criteria. One thousand two hundred and fifty-two patients were included. Our study showed that exposure to rufinamide was associated with a significant increase in risk of somnolence [relative ratio (RR) 1.87; 95% confidence interval (CI) 1.33, 2.62; P = 0.0003], dizziness (RR 2.66; 95% CI 2.00, 3.55; P = 0.00001), fatigue (RR 2.14; 95% CI 1.57, 2.91; P = 0.01) and headache (RR 1.28; 95% CI 1.02, 1.59, P = 0.03). In addition, exposure to rufinamide was associated with higher treatment discontinuation rates as compared with placebo (RR 2.65; 95% CI 1.74, 4.03; P = 0.00001).

Conclusions

The risk of CNS adverse events appears to be increased in patients exposed to rufinamide as well as the treatment discontinuation rates. However, although statistical associations were significant, additional long term safety studies are required to confirm the clinical significance of these findings, as most reports described only mild and moderate adverse events.     

Rufinamide for the treatment of Lennox–Gastaut syndrome

Introduction: Lennox–Gastaut syndrome (LGS) is a severe treatment-resistant childhood-onset epilepsy. This review examines the role of the new drug rufinamide for the treatment of LGS.

Areas covered: MEDLINE and Google Scholar searches were undertaken. The pharmaceutical company was contacted for the latest information. LGS is characterized by the triad of diffuse slow spike–wave discharges in the electroencephalogram (EEG), learning disability (mental retardation) and frequent generalized seizures of multiple types, usually including tonic, atonic and atypical absence seizures. Felbamate, lamotrigine and topiramate have resulted in significant reductions in some seizure types, but no treatment has achieved acceptable seizure control in most patients. In a pivotal randomized, double-blind, placebo-controlled trial, the new drug rufinamide achieved significant improvements in seizure control in previously resistant subjects when added to up to three concomitant antiepileptic drugs. Open studies including patients with LGS have also demonstrated efficacy. These trials and a large open trial in adults and adolescents with partial seizures have revealed no serious adverse effects so far. The most common adverse events were fatigue/somnolence and vomiting. Rufinamide is of value in decreasing seizure frequency in LGS, but seizure freedom is seldom achieved. Although no serious adverse effects have been identified, the limited data available at present allow no firm conclusions to be drawn with regard to safety.

Expert opinion: The data support a role for rufinamide in treating LGS. However, more efforts are required to provide antiepileptic drugs for this treatment-resistant epilepsy syndrome. Rufinamide might also be of value in treating other forms of epilepsy.     

Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome

Background: To report on the first multicenter Italian experience with rufinamide as adjunctive drug in children, adolescents and young adults with refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Methods: Thirty‐eight patients (19 males, 19 females), aged between 4 and 34 (mean 13.7 ± 8.3, median 12.5), all affected by different types of childhood‐onset refractory epileptic encephalopathies other than Lennox–Gastaut syndrome, were treated with rufinamide as adjunctive drug for a mean period of 11.4 months (range 3–26 months). Results: Fifteen of 38 patients (39.5%) had a ≥50% seizure reduction in countable seizures. Complete seizure freedom was achieved in one of these patients (2.6%). Three patients (7.9%) had a 25–49% seizure reduction, whilst seizure frequency remained unchanged in 15 (39.5%) and increased in five patients (13.1%). Eleven patients (28.9%) reported adverse side effects. Vomiting was reported in five patients (13.1%); drowsiness, decreased appetite and irritability with migraine manifested in other four patients. They were transient and mild in all cases. Conclusion: Rufinamide may be an effective and well‐tolerated adjunctive drug for the treatment of refractory childhood‐onset epileptic encephalopathies other than Lennox–Gastaut syndrome. Rufinamide was most effective in patients with drop‐attacks and (bi)frontal spike–wave discharges.