Therapeutic Drug Monitoring for Rufinamide in Japanese Patients With Epilepsy: Focus on Drug Interactions, Tolerability, and Clinical Effectiveness

Background: The purposes of this study were to assess drug interactions between rufinamide and concomitant antiepileptic drugs (AEDs) and to identify the therapeutic window for rufinamide. Methods: Serum samples (n = 1531) were obtained from 178 patients (aged 2-57 years), and clinical records were retrospectively reviewed to evaluate the safety and efficacy of rufinamide (mean observation time, 1073 +/- 846 days). Results: Rufinamide exhibited linear pharmacokinetics at doses of up to 60 mg/kg (range, 50-3200 mg/d). Concomitant use of the enzyme-inducing AEDs such as phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. Clinical response was seen in 41 patients (23.0%), with a median therapeutic concentration (interquartile range) of 20.6 mcg/mL (13.3-27.0). There was no difference in the therapeutic concentrations between seizure types, but patients with tonic/atonic seizures tended to have higher rufinamide concentrations. During the study period, adverse events were reported in 64 patients (35.8%), including somnolence, gastrointestinal disorders, dizziness, and irritability/behavior disorders. Conditional logistic regression analysis showed that patients administered a concentration greater than 20 mcg/mL had an 8.6-fold higher incidence of adverse events. Conclusions: Therapeutic drug monitoring for rufinamide is clinically useful for predicting drug interactions between rufinamide and concomitant AEDs. When a patient has tonic/atonic seizures, careful titration is required for concentrations greater than 20 mcg/mL.