The Influence of Dosage, Age, and Comedication on Steady State Plasma Lamotrigine Concentrations in Epileptic Children

The effects of age, dosage, and type of comedication on plasma lamotrigine (LTG) concentrations and the relationship between plasma drug levels and clinical response were evaluated in a prospective study of 45 patients, aged 3 to 38 years, with epilepsy uncontrolled by conventional anticonvulsant therapy. Six of the 45 patients were on single-drug therapy, and 39 were on two to five concurrently administered antiepileptic drugs when LTG was added. Thirteen patients were assessed at three or more LTG dosage levels. Within individuals, steady state plasma LTG concentrations increased linearly with increasing daily dosage over the examined dose range (25 to 575 mg/day or 0.75 to 21 mg/kg.day). Among patients also receiving enzyme-inducing agents, such as carbamazepine, barbiturates, or phenytoin, plasma LTG concentrations normalized to a 1 mg/kg daily dose were lower in children aged 3 to 6 years (0.30 +/- 0.17 microgram/ml; n = 6) than in the older children (0.43 +/-0.18 microgram/ml; n = 12) and adolescents/adults (0.68 +/- 0.26 microgram/ml; n = 10). In patients treated with valproate, the age dependency of plasma LTG was less evident, possibly because of a smaller sample size and the confounding effect of comedication. Within any given age group, dose-normalized LTG concentrations were about five-fold higher in patients comedicated with valproic acid than in those comedicated with enzyme inducers. Twenty patients showed a favorable response (with a > or = 40% reduction in seizure frequency compared with the pre-LTG period) and continued on long-term treatment. Plasma drug concentrations in these apparent responders were highly variable and did not differ significantly from those observed in nonresponders (6.6 +/- 5.2 versus 4.8 +/- 3.3 microgram/ml). These findings show that plasma LTG concentrations exhibit a wide interindividual variability under the influence of age and type of comedication, but they are predictably related to dosage within individual patients. Although there was no apparent relationship between drug levels and clinical response in this difficult-to-treat population, further studies on the potential value of monitoring plasma LTG concentrations are indicated.