PDF of poster

Objectives: A double-blind, placebo-controlled, ascending multiple dose study was performed to evaluate the cardiovascular safety, the tolerability, and the pharmacokinetics of rufinamide and determine the maximum tolerated dose in healthy subjects.

Methods: Fifteen healthy subjects received multiple ascending doses of rufinamide at 6 dose levels from 800 to 7200 mg per day.  Drug was administered b.i.d. with a standardized meal as 400 mg film coated tablets over a period of 18 days with dose increases every 3 days.  Five subjects received equivalent numbers of placebo tablets over 18 days.  A predose PK sample was taken at the start of the study and nine PK samples were collected on the last day of dosing at each dose level giving a total of 55 samples per subject. 71 ECG/ subject were recorded before and during treatment. Population modelling of concentration and of ECG data was sequential, using NONMEM. Drug effect was estimated on heart rate and corrected QT (QTcF and study/subject specific (QTcSS)).

Results and conclusion: A one-compartment model with first-order absorption and elimination was used to predict the concentration data. Bioavailability decreased as dose increased.  The effect of the dose on the bioavailability was described with an E_max model. Heart rate increased in placebo and rufinamide treated subjects. Using uncorrected QT, QTcF or QTcSS, rufinamide did not increase QT. On the contrary, rufinamide produced a small decrease of QT, QTcF and QTcSS, proportional to rufinamide concentration. For each 1 mg/mL, rufinamide decreased QTcSS by 0.5 ms, which equates to a decrease of 7.5 ms at a typical concentration in patients (15 mg/mL). The PK variability between subjects was very low and even with such a small sample size; NONMEM provided precise estimates of all parameters. The cardiovascular tolerability was excellent. Rufinamide was associated with a small decrease in QTcSS.