Understanding the variability in clinical response to rufinamide, a new antiepileptic drug: a pooled PKPD analysis

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Background: Rufinamide is a new chemical entity developed for the treatment of epilepsy that modulates the activity of sodium channels, prolonging their inactive state.  In phase II and phase III studies, rufinamide significantly reduced seizure frequency.

Objective: The objective of this analysis was to describe the exposure response (ER) relationship in patients with epilepsy (paediatric patients and adults) across a variety of doses, formulations, and concomitant anti-epileptic medications, over 10 years of development (1990-2000).

Methods: Studies were multicentre, double-blind, placebo-controlled (except for two studies), randomised, parallel-group, in patients with partial seizures, generalised seizures, and Lennox-Gastaut syndrome.  Rufinamide was administered as oral tablets with different formulations, at daily doses: 100 to 7200 mg.  In 6/7 studies, the clinical endpoint was seizure frequency, whereas one study endpoint was the time to meet one exit criteria.  Seizure frequency was collected using diaries.  Population PK and PKPD modelling used NONMEM.  The analysis of total seizure frequency was performed after Log_e transformation of frequency per day. 

Results: The PK population included 1072 patients.  The PKPD population included 1725 patients (half males), with a total of 9881 PD observations.  A one-compartment disposition model described rufinamide pharmacokinetics.  The natural logarithm of total seizure frequency was described by the sum of an intercept (baseline frequency- prior to treatment initiation and at zero concentration of rufinamide), the effect of placebo and time in the study and a decrease proportional to rufinamide C_avss.  Efficacy ER was not affected by formulation, study design (for identical endpoint) or concomitant medications.  Differences in response among studies were explained by the relative bioavailability between formulations, by the baseline disease severity, and by the differences in placebo response between populations (children, adolescent, and adults).

Conclusions: This PKPD analysis allowed a complete bridging between formulations/doses, and a complete bridging between populations (adults and children) over 10 years of development.