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

Abstract: 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<0.0001). Our findings in the group of children with Lennox-Gastaut syndrome are encouraging. Thirteen patients with Lennox-Gastaut syndrome showed an overall improvement when LTG was added. Seven of the 20 children responded with a more than 50% seizure reduction. Two patients became seizure-free and three showed a more than 75% reduction in seizure frequency. Assessments of the short-term effects of AEDs by measuring free amino acids in the CSF are problematic, both methodologically and ethically. We could not find any changes in amino acid levels when LTG was added. Video-EEG may be a complementary method for assessing AED efficacy in children with frequent epileptiform discharges in the EEG. Our findings support the assumption that reduction of the amount of interictal epileptiform activity and/or periods of more than 30s of repetitive, epileptiform discharges is a possible reason for the observed improvement in behaviour. Measures of seizure severity and quality of life are of great importance in assessing the efficacy outcome when a new AED is studied. Therapeutic decisions based only on seizure frequency are not sufficient for adequate management of patients with epilepsy. Increased alertness, resulting in a corresponding improvement in social interaction and educational progress, is as important as a reduction of clinical seizures. Altogether, these results have important implications for practical patient management. Failure to control clinical seizures does not necessarily mean complete failure of the treatment.