Investigation of the metabolism of rufinamide and its interaction with valproate.

Rufinamide was evaluated in vitro to determine which enzyme(s) are responsible for rufinamide hydrolysis and whether valproate, one of its metabolites (valproyl-CoA), and/or the rufinamide hydrolysis product (CGP 47292) could inhibit hydrolysis. Rufinamide hydrolysis was mediated primarily by human carboxylesterase (hCE) 1 and was nonsaturable up to 500 µM. Two-thirds of rufinamide hydrolysis was estimated to occur in human microsomes and one-third in cytosol. Valproate was a selective inhibitor for hCE1 compared to hCE2 and inhibition had a greater impact on rufinamide hydrolysis in microsomes than in cytosol. Valproyl-CoA caused similar inhibition of rufinamide hydrolysis in both microsomes and cytosol. Carboxylesterases were not significantly inhibited by CGP 47292. Inhibition of in vitro rufinamide hydrolysis by valproate could offer an explanation for the observed in vivo drug-drug interaction between the two antiepileptic drugs.

Rufinamide from clinical trials to clinical practice in the United States and Europe.

Rufinamide is a triazole derivative structurally unrelated to other antiepileptic drugs that is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4 years. Originally granted orphan drug status, marketing authorisation was obtained on the basis of a randomised, double-blind, placebo-controlled trial conducted in 138 LGS patients. An open-label extension study subsequently demonstrated that rufinamide's efficacy and tolerability were maintained over the longer term (median duration of treatment, 432 days). Recently published reports from Europe and the United States have described the use of adjunctive rufinamide to treat LGS in clinical practice. These data complement the clinical trial results, by providing information on the efficacy and tolerability of rufinamide when used on an individualised basis in real-world practice, under less tightly restricted conditions in terms of patient population and dosing strategies. A comparison of the data reveals that a "lower and slower" dosing strategy tends to be adopted in clinical practice, in comparison with the clinical trial, which does not appear to compromise efficacy, but may provide improvements in tolerability. Individual case reports provide additional valuable information on how rufinamide is being used to treat different seizure types associated with LGS. Since clinical experience with rufinamide is currently at an early stage, there are still unanswered questions relating to its use, and it is likely that its place in the adjunctive treatment of LGS will evolve as further data emerge.

Bioavailability of three rufinamide oral suspensions compared with the marketed 400-mg tablet formulation: results from a randomized-sequence, open-label, four-period, four-sequence crossover study in healthy subjects.

BACKGROUND: Rufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years. OBJECTIVES: The primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (reference) with 10 mL of a newly developed 40-mg/mL suspension (test) manufactured using 3 different homogenization speeds in healthy subjects under fed conditions. The study also explored whether homogenization speed had any effect on rufinamide pharmacokinetics when administered as a suspension formulation. METHODS: This was a randomized, open-label, crossover, single-dose study in healthy, fed subjects aged 18 to 55 years (inclusive), conducted at a single center in the United Kingdom. Subjects were randomized to 1 of 4 treatment sequences, with each sequence consisting of 4 treatment periods. In each treatment period, subjects received a single dose of either the reference product (400-mg rufinamide tablet) or the test product (10 mL of rufinamide suspension [40 mg/mL] manufactured using 3 different homogenization speeds [1800, 2100, and 3000 revolutions per minute (rpm)]). Serial blood samples were collected for 72 hours after dosing for the measurement of rufinamide in plasma. Primary comparisons between test (suspension) and reference (tablet) formulations focused on AUC from 0 to 72 hours (AUC(0-72 h)) and C(max). The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90% CIs of AUC(0-72 h) and C(max) were within the predetermined range of 80%-125%, according to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) requirements. Tolerability was assessed by subject interviews, physical examinations, and laboratory tests. RESULTS: Twenty-four healthy subjects were randomized: 8 were male and 16 were female; 22 white, 1 black, and 1 Asian subjects were enrolled. Mean (SD) age was 29.8 (10.0) years. Mean weight was 68.2 (11.0) kg, and mean body mass index was 23.6 (3.0) kg/m(2). Twenty-one subjects completed the study; 2 subjects discontinued because of adverse events (both urinary tract infections considered unrelated to treatment) and 1 because of protocol deviation. The 72-hour pharmacokinetic data for the last complete treatment period before discontinuation were included in group means. The geometric least squares mean C(max) value for the reference tablet formulation was 4840.24 ng/mL; and 4254.87, 4204.29, and 4418.44 ng/mL for the 1800-, 2100-, and 3000-rpm test suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for C(max) were 0.88 (90% CI, 0.84-0.92), 0.87 (0.83-0.91) and 0.91 (0.88-0.95) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The geometric least squares mean AUC(0-72 h) values were 75,960.48 ng · h/mL for the tablet formulation and 74,279.02, 73,746.03, and 73,701.17 ng · h/mL for the 1800-, 2100-, and 3000-rpm suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for AUC(0-72 h) were 0.98 (90% CI, 0.95-1.00), 0.97 (0.95-1.00) and 0.97 (0.95-0.99) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The ratios and associated 90% CI limits (for test suspensions to the reference tablet) for AUC(0-72 h) and C(max) were within the FDA and EMA criteria for assuming bioequivalence to the 400 mg tablet. Comparisons among the 3 rufinamide test suspensions also met the regulatory criteria for assuming bioequivalence to one another. Treatment-emergent adverse events (TEAEs) were experienced by 18.2% (4/22) of subjects treated with the 400-mg tablet, 21.7% (5/23) of subjects treated with the 1800-rpm suspension, 26.1% (6/23) of subjects treated with the 2100-rpm suspension, and 8.7% (2/23) of subjects treated with the 3000-rpm suspension. Overall, 54.2% (13/24) of subjects experienced a TEAE; all TEAEs were mild or moderate in severity, with headache being the most frequently reported (37.5% [9/24]). There were no serious adverse events or deaths. CONCLUSION: This single-dose study in a small population of fed, healthy subjects found no statistically significant differences in relative bioavailability among each of the 3 test suspensions and the currently marketed 400-mg tablet formulation of rufinamide, meeting FDA and EMA regulatory requirements for assuming bioequivalence.

A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures.

PURPOSE: Efficacy and safety of adjunctive rufinamide (3,200 mg/day) was assessed in adolescents and adults with inadequately controlled partial-onset seizures receiving maintenance therapy with up to three antiepileptic drugs (AEDs). METHODS: This randomized, double-blind, placebo-controlled, parallel-group, multicenter study comprised a 56-day baseline phase (BP), 12-day titration phase, and 84-day maintenance phase (MP). The primary efficacy variable was percentage change in total partial seizure frequency per 28 days (MP vs. BP). Secondary efficacy outcome measures included ≥50% responder rate and reduction in mean total partial seizure frequency during the MP. Safety and tolerability evaluation included adverse events (AEs), physical and neurologic examinations, and laboratory values. Pharmacokinetic and pharmacodynamic assessments were conducted. RESULTS: Three hundred fifty-seven patients were randomized: 176 to rufinamide and 181 to placebo. Patients had a median of 13.3 seizures per 28 days during BP; 86% were receiving ≥2 AEDs. For the intent-to-treat population, the median percentage reduction in total partial seizure frequency per 28 days was 23.25 for rufinamide versus 9.80 for placebo (p = 0.007). Rufinamide-treated patients were more than twice as likely to have had a ≥50% reduction in partial seizure frequency (32.5% vs. 14.3%; p < 0.001) and had a greater reduction in median total partial seizure rate per 28 days during the MP (13.2 vs. 5.2; p < 0.001). Treatment-emergent AEs occurring at ≥5% higher incidence in the rufinamide group compared with placebo were dizziness, fatigue, nausea, somnolence, and diplopia. CONCLUSIONS: Adjunctive treatment with rufinamide reduced total partial seizures in refractory patients. AEs reported were consistent with the known tolerability profile of rufinamide.

A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures.

OBJECTIVE: To assess the efficacy, safety, tolerability, and pharmacokinetics of adjunctive rufinamide in adults and adolescents with inadequately controlled partial seizures receiving treatment with one to three concomitant antiepileptic drugs (AEDs). METHODS: A 24-week multicenter Phase II clinical study was conducted (n=647), comprising a 12-week prospective baseline phase and a 12-week randomized double-blind, parallel-group, five-arm (placebo and rufinamide 200, 400, 800, and 1600mg/day) treatment phase. RESULTS: The linear trend of dose response for seizure frequency per 28 days in the double-blind treatment phase - the primary efficacy outcome measure - was statistically significant in favor of rufinamide (estimated slope=-0.049, P=0.003; minimally efficacious dose, 400mg/day). Response rates, defined as a >or=50% reduction in seizure frequency per 28 days, also revealed a significant linear trend of dose response (P=0.0019, logistic regression analysis). Adverse events were comparable between placebo and all rufinamide groups except the 1600mg/day group; no safety signals were observed. CONCLUSIONS: These results suggest that in the dose range of 400-1600mg/day, add-on rufinamide therapy may benefit patients with inadequately controlled partial seizures and is generally well tolerated. These data also suggest that higher doses may confer additional efficacy without adversely affecting safety and tolerability.

Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies.

Rufinamide is a novel antiepileptic agent recently approved in the United States for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. To help inform clinical decision making, the authors analyzed safety and tolerability data from the entire pediatric population in the rufinamide epilepsy clinical development program. The analysis population comprised 212 rufinamide-treated (age range 3-16 years) and 197 placebo patients (age range 4-17 years) in the double-blind studies, and 391 patients receiving rufinamide in the double-blind and/or open-label extensions. The most common adverse effects observed in rufinamide-treated patients in the double-blind studies were somnolence, vomiting, and headache. Changes in laboratory values, vital signs, and weight were generally clinically insignificant. This pooled analysis of data from pediatric patients in clinical studies of rufinamide for the treatment of seizures, mainly as adjunctive therapy, suggests a favorable safety and tolerability profile in this patient population.