Rufinamide in Children with Refractory Epilepsy: Pharmacokinetics, Efficacy, and Safety

Abstract

We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady-state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 ± 22.0 µmol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%).

Retention rates of rufinamide in pediatric epilepsy patients with and without Lennox–Gastaut Syndrome

“…Limitations common to several previously published post-marketing observational studies of RFM in refractory epilepsy include short follow up times, variable or unspecified time points for efficacy assessment, small sample sizes, populations restricted to one epilepsy type, and the retrospective use of the 50% responder rate outcome measure (Dahlin and Ohman, 2012; Joseph et al, 2011; Kim et al, 2013, 2012; Kluger et al, 2009; Mueller et al, 2011; Olson et al, 2011; Thome-Souza et al, 2014; Vendrame et al, 2010). Particularly in studies reporting efficacy at short assessment times, “honeymoon periods” may not be distinguishable from sustained efficacy, which limits the impact of those studies on clinical decision making.…”

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

“…In one clinical trial, the plasma concentration ranged from 5.0 to 48.2 mcg/mL (20.9 ± 202.3 µmol/L) during the maintenance period. 6 In addition, Dahlin et al 7 reported that 12 of 51 pediatric patients with refractory epilepsy (23.5%) responded to rufinamide and had a mean concentration of 8.8 ± 5.2 mcg/mL (36.9 ± 22.0 µmol/L). A pooled analysis of clinical trials showed a positive correlation between reduction in seizure frequency and steady-state plasma rufinamide concentrations.…”