Abstracts

To evaluate the potential effect of rufinamide on the pharmacokinetics (PK) of 6 concomitantly administered antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate. Data were analyzed from 5 multicenter, double-blind, placebo-controlled, randomized, parallel-group studies of pediatric and adult patients with inadequately controlled seizures treated with 1 to 3 AEDs. Rufinamide or placebo treatment duration varied from 39 to 140 days, according to study, with baseline periods from 28 days to 3 months. Dosages of concomitant AEDs were kept constant from baseline throughout the duration of each study. Blood samples to measure concomitant AED concentrations were collected before, during, and after treatment with rufinamide or placebo. Data were standardized across all studies and pooled to produce a single data set. Population PK analysis used non-linear mixed effect modeling (NONMEM). The clearance of a linear PK model was estimated for each AED; age was used as the scaling factor to adjust clearance among children, adolescents, and adults for carbamazepine, topiramate, and valproate, and weight was used as the scaling factor for lamotrigine, phenobarbital, and phenytoin. Six populations of rufinamide patients with concomitant AEDs were analyzed: (1) carbamazepine, n=903, median age 32.3 years (range 3.9-68.8 y); (2) lamotrigine, n=200, median age 22.7 years (range 4.7-68.5 y); (3) phenobarbital, n=149, median age 34.5 years (range 4.3-62.6 y); (4) phenytoin, n=299, median age 34.4 years (range 4.5-72.3 y); (5) topiramate, n=69, median age 15.6 years (range 4.1-53.7 y); (6) valproate, n=488, median age 27.2 years (range 4.3-68.6 y). The clearance of topiramate and valproate was not modified by rufinamide. The clearance of carbamazepine and lamotrigine was increased and the clearance of phenobarbital and phenytoin was decreased as a function of rufinamide plasma concentration. Rufinamide-induced changes in AED clearance were similar across age groups. At a rufinamide plasma concentration of 15 [mu]g/mL (representing the average steady-state concentration in a typical patient at doses of 45 mg/kg per day in children and 3200 mg/d in adults), the percent change in AED clearance was less than 18% of values without rufinamide. None of the clearance changes for the concurrent AEDs would result in changes of steady-state AED concentrations greater than 21% in typical subjects. The magnitude of rufinamide effects on the PK parameters of concomitantly administered AEDs is unlikely to be of clinical significance. The effect of rufinamide on clearance of carbamazepine, lamotrigine, phenobarbital, and phenytoin did not differ with age. (Supported by Eisai Inc.)