Abstracts

Rufinamide, a new antiepileptic drug (AED) under investigation, has demonstrated efficacy as adjunctive treatment for patients with inadequately controlled partial seizures. This study was conducted to assess the safety and characterize the pharmacokinetic (PK) profile of ascending doses of rufinamide in pediatric patients with inadequately controlled seizures who were receiving 1 to 2 other concomitant AEDs. Patients with inadequately controlled seizures were assigned to 1 of 3 groups based on age (Group I: [le]6 years, Group II: 7 to 12 years, or Group III: 13 to [lt]18 years) and were given open-label rufinamide in weekly ascending doses. Rufinamide was administered orally in equally divided doses over 14 days at a starting dosage of approximately 10 mg/kg per day BID (Days 1-7), and then increased to 30 mg/kg per day (Days 8-14). A dosage reduction to 20 mg/kg per day was allowed for patients who could not tolerate the 30 mg/kg per day dosage level. Safety assessments included routine laboratory testing and evaluation of adverse events (AEs), electrocardiograms (ECGs), vital signs, and physical examinations. A 12-hour PK profile was obtained on Days 7 and 14. Sixteen patients entered and completed the study. There were no significant differences between any 2 age groups for the following PK parameters: area under the curve between 0 to 12 hours (AUC[sub]0-12h[/sub]), steady-state maximum concentrations (C[sub]maxss[/sub]), and steady-state minimum concentrations (C[sub]minss[/sub]). A 2- to 2.5-fold increase in AUC[sub]0-12h[/sub], C[sub]maxss[/sub], and C[sub]minss[/sub] was observed with a dosage increase from 10 to 30 mg/kg per day, which may be attributed to saturable absorption or limited solubility at higher doses. All AEs were mild to moderate in severity. The most frequently reported AEs were nervous system-related (n=6, 37.5%) and included agitation, somnolence, ataxia, headache, and aggressive reaction. Digestive system-related AEs were also frequently reported (n=3, 18.8%) and included nausea, abdominal pain, and vomiting. One serious AE (increased seizures) was reported that was not considered study drug-related. Two patients had clinically notable decreases in pulse rate, but no significant symptomatology was reported for either patient. No other clinically relevant effects were observed during the study. Adverse events seen in this pediatric population were mild to moderate in severity. Rufinamide did not demonstrate first-order linear PK, since a 3-fold increase in dose provided only a 2- to 2.5-fold increase in AUC[sub]0-12h[/sub], C[sub]maxss[/sub], and C[sub]minss[/sub]. Rufinamide is well tolerated in pediatric patients at both the 10- and 30-mg/kg per day dosages. (Supported by Eisai Inc.)