Abstracts

The objective of this study was to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and dose-response relationships of rufinamide as adjunctive therapy in patients with inadequately controlled seizures associated with ennox Gastaut syndrome. Pharmacokinetic and PD data were collected from rufinamide-treated and placebo patients participating in a double-blind, placebo-controlled, randomized, parallel-group 84-day study. Blood samples were collected to determine rufinamide plasma levels at Visits 4 and 6 (Days 28 and 84) of treatment, or when a patient was discontinued from the trial. Adverse events (AEs) reported by [ge]10% of patients in either treatment group were considered for the analysis. For population PK and PK/PD analyses, non-linear mixed effects modeling (NONMEM) was used with first-order estimation and first-order conditional estimation methods. Rufinamide efficacy variables were based on the total seizure frequency and tonic-atonic seizure frequency as indicated in a seizure diary. A total of 65 patients were included in the PK analysis and 129 in the PK/PD analysis. PK data were described by a 1-compartment model. Clearance (CL) increased linearly with increased body surface area independent of patient age, sex, or race. Apparent CL in adults was 6.65 L/h, adolescents 4.51 L/h, and children 2.77 L/h, and was unaffected by liver and kidney function. In general, children had a higher average steady-state concentration (C[sub]avss[/sub])[sub] [/sub]than adolescents and adults due to a lower rufinamide CL and higher administered dose per kilogram. Rufinamide bioavailability decreased with increasing doses. Of the coadministered antiepileptic drugs (AEDs) analyzed (lamotrigine, topiramate, and valproate), only valproate significantly affected rufinamide CL, producing a 40% increase in rufinamide C[sub]avss[/sub] in children and 11% increase in adults. Log-transformed total seizure frequency and tonic-atonic frequency were shown to decrease proportionally with increasing rufinamide concentrations. These relationships were not affected by concomitant treatment with valproate, lamotrigine, clonazepam, or topiramate or patient baseline characteristics. Rufinamide significantly improved the global evaluation of seizure severity, in a concentration-dependent manner. None of the concomitant AEDs or other covariates evaluated affected the PK/PD relationship. Rufinamide exposure had no relationship to AEs occurring in [ge]10% of the patients in either treatment group. Rufinamide oral bioavailability decreased with increasing doses, and CL was proportional to body surface area. Coadministration of valproate led to a moderate reduction in rufinamide CL, but lamotrigine and topiramate did not affect this parameter. Rufinamide efficacy was linearly related to concentration, but the frequency of AEs was unaffected. (Supported by Eisai Inc.)