Supporting the recommended paediatric dosing regimen for rufinamide using clinical trial simulation
Mathilde Marchand (1, 2), Eliane Fuseau (1), David Critchley (3)
(1) EMF consulting, Aix en Provence, France; (2) EA3286 Laboratoire de Toxicocinétique et Pharmacocinétique, Marseille, France; (3) EISAI Global Clinical development, UK
Background: Rufinamide marketing application was reviewed recently by the CHMP (Committee for medicinal products for human use), for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) as adjunctive therapy in patients 4 years and older. Relationships between pharmacokinetics, efficacy and safety parameters have been established. However, only one study had been conducted in patients with Lennox-Gastaut syndrome. To document the exposure in a larger population, simulations of exposure and efficacy under the proposed dosing regimen were performed, so that the main sources of variability could be understood and dosing regimens found to give exposure similar to that shown to be safe and efficacious in larger populations of patients with others types of epilepsy.
Methods: Monte Carlo simulations were used to investigate the effect on rufinamide exposure and efficacy in the patient population of different proposed dosing regimens. Four dosing regimens, varying in term of initial dose, dose increment and maximum daily dose were defined based on patient body weight from 4 to 35 years of age. Since exposure variability appeared to increase in children with body weight less than 30 kg, additional simulations of exposure were carried out in that population.
Results/Conclusions: The simulations of the different dosing regimen resulted in rufinamide exposure similar to that observed during clinical trials. The results of the simulated total seizure frequency per day show a large variability, which was also observed in the LGS clinical study. The concentrations simulated in patients with a body weight less than 30 kg presented a large interindividual variability than other patients. Additional simulations demonstrated that this increased variability was due to greater valproate concentration in some of the children treated with rufinamide. Complementary investigations of maximum daily dose lead to propose maximum daily dose for patients less than 30 kg receiving antiepileptic drugs: rufinamide and valproate. This recommendation would ensure that children (less than 30 kg) treated with rufinamide and valproate concomitantly would not be overexposed to rufinamide.