A pharmacokinetic and pharmacodynamic study of an antiepileptic drug (lamotrigine) in young patients with drug-resistant generalized epilepsy

The purpose of the present study was to investigate the safety and efficacy of lamotrigine in young patients with drug-resistant generalised epilepsy. This group of patients is difficult to study due to a high seizure frequency, comorbidity and the frequent use of polytherapy. "Drug-resistant" was defined as not being seizure-free despite consecutive treatment attempts of adequate duration and with adequate therapeutic doses of at least three conventional AEDs. "Generalised" was defined according to the definition of the International League Against Epilepsy requiring a scalp EEG showing generalised or multifocal epileptiform activity. Thirty consecutive patients, 15 boys and 15 girls, satisfied the inclusion criteria and took part in the study. The mean age at entry was 9.9 years (range 2.5-22 years) and the median duration of epilepsy at entry was 8.3 years (range 1.4-19.1 years). The mean number of seizures per month at entry was 102 (range 4-315), and the patients (n=30) were treated with 19 different AED combinations. Four patients had normal IQs, 9 patients showed mild mental retardation (MR) and 17 showed severe MR with IQs lower than 50. Twenty-one patients could be said to have epileptic syndromes: one child with juvenile myoclonic epilepsy and 20 children with Lennox-Gastaut syndrome. Our patients had one to five types of seizure. Our enrichment study model presented several advantages. The dose was adjustable to age, bodyweight and co-medication. The lowest effective dose was used, which is similar to how patients with epilepsy are treated in clinical practice. Ethically, all patients were able to try the new drug and only clinical "responders- would continue in a double-blind crossover study with placebo. Ths trial minimised the exposure of children to placebo. We found no relationship between plasma LTG concentrations and clinical efficacy. However. our results suggest that therapeutic drug monitoring (TDM) of LTG is of value for optimising the dose because of large interindividual differences caused by interactions between LTG and other AEDs. TDM may also be of great importance, especially in patients with rapid elimination who may require medication three times daily to ensure optimal treatment with LTG. We found LTG to be more effective than placebo when we looked at the average monthly seizure frequency (p