DIFFERENTIAL EFFECTS OF RUFINAMIDE IN ADULTS WITH PARTIAL ONSET SEIZURES AS A FUNCTION OF CONCOMITANT ANTIEPILEPTIC DRUG THERAPY: A POST-HOC ANALYSIS [P05.091]

Martin Brodie, Glasgow, United Kingdom; Honglan Li, Wenquan Wang, Milind Narurkar, Sharon Richardson, Woodcliff Lake, NJ

Rufinamide is a novel antiepileptic drug (AED) that is currently approved for adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome. Rufinamide is thought to slow the rate of sodium-dependent nerve impulses by maintaining voltage-dependent sodium channels in an inactive state.¹ Some research has suggested that rufinamide may be effective for the treatment of partial seizures in adults.² In this poster, Brodie et al described their post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial in which patients with treatment-refractory partial seizures used rufinamide in combination with other AEDs.

Patients older than 16 who were diagnosed with partial seizures first went through an 8-week baseline phase during which they were maintained on stable doses of 1 or 2 AEDs (usually carbamazepine, valproate, lamotrigine, or phenytoin; a few patients received gabapentin). Approximately 70% of patients used 2 concomitant AEDs, and most of the patients used regimens that included carbamazepine. Patients with at least 6 documented seizures during the baseline phase then continued using their baseline AED regimens and were randomized to double-blind adjunctive treatment with rufinamide (titrated to a maximum daily dose of 3200 mg in 2 divided doses) or twice-daily placebo for up to 13 weeks.

Outcome measures included the change in seizure frequency from baseline and the proportion of patients who were considered to have responded to therapy (with treatment response defined as a reduction of seizure frequency of at least 50% from baseline). For the study population as a whole, the median seizure frequency decreased by 20.4 seizures per 28-day period for patients who received adjunctive rufinamide, whereas the seizure frequency increased by a median of 1.6 seizures per 28 days for patients in the placebo group (P = .02). The proportion of patients who responded to treatment was also significantly higher with rufinamide than with placebo for the overall study population (28.2% vs 18.6%; P = .038).

In the post-hoc analysis reported in this poster, certain AEDs administered concomitantly with rufinamide produced less of a reduction in seizure frequency from baseline than when rufinamide was administered in combination with other medications. For example, the seizure rate decreased by 12.3% with rufinamide versus an increase of 1.8% with placebo in the subgroup of patients whose AED regimens included carbamazepine. The difference between rufinamide and placebo in these patients was not statistically significant. However, in patients who were not using carbamazepine, rufinamide produced a 29.2% reduction in seizure rate from baseline, compared with an increase of 0.7% with placebo, a statistically significant difference (P = .05). Similar outcomes were observed for concomitant lamotrigine and phenytoin. An exception to this trend was observed when rufinamide was administered with concomitant valproate, a combination that appeared to increase the effectiveness of rufinamide. The median seizure rate decreased by 37.6% from baseline in patients who received rufinamide in combination with valproate versus 13.2% for patients who used rufinamide in regimens without valproate (P = .018).

It is not clear why concomitant carbamazepine or lamotrigine apparently decreased the efficacy of rufinamide in adult patients with treatment-refractory partial seizures. The investigators suggested that these AEDs may produce significant pharmacodynamic or pharmacokinetic interactions when used with rufinamide, and they concluded that the potential for these drug interactions should be considered in future clinical studies of rufinamide.

References
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2. Hakimian S, Cheng-Hakimian A, Anderson GD, Miller JW. Rufinamide: a new anti-epileptic medication. Expert Opin Pharmacother. 2007;8:1931-1940.