Dose–response population analysis of levetiracetam add-on treatment in refractory epileptic patients with partial onset seizures

SummaryIn this post hoc analysis, individual seizure counts from four double-blind trials of adjunctive treatment with levetiracetam were analyzed by non-linear mixed-effects modeling (NONMEM). First, a model was fitted to the individual count data assuming a Poisson distribution, in order to classify the patients as either improving or deteriorating from baseline. In the second stage, the dose–response relationship in improving patients was determined by fitting the data to an Emax model including a placebo effect. The percentage of improvers was 59% on placebo and 73%, 74%, 77% and 73% on levetiracetam 1, 2, 3 and 4 g/day, respectively. The ED50 of 1408 mg/day was close to the current WHO Defined Daily Dose of levetiracetam (1500 mg). The maximum recommended dose of 3000 mg/day was predicted to reduce seizures by ≥90% in 10% of improving patients. Age, gender, body weight, race, and number of concomitant antiepileptic drugs neither affected the percentage of responders nor the extent of change in seizure frequency from baseline.