Single-dose pharmacokinetics of lamotrigine in children: Influence of age and antiepileptic comedication

To evaluate the influence of pediatric age and antiepileptic comedication o n the single-dose pharmacokinetics of lamotrigine, 19 patients with epileps y (10 comedicated with enzyme inducers and 9 comedicated with valproic acid ) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by hi gh-performance liquid chromatography. Pharmacokinetic parameters were calcu lated by noncompartmental analysis. Lamotrigine half-life (T-1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those re ceiving valproic acid (T-1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas C,,, and T,,, values were comparable in the two groups. The differe nces in pharmacokinetic parameters persisted when comparisons were made wit hin subgroups stratified according to age. Within groups of patients homoge neous for type of comedication, C-max and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no signi ficant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokineti cs. The reduction in lamotrigine concentrations caused by enzyme inducers a nd the elevation caused by valproic acid can be explained by stimulation an d inhibition, respectively, of lamotrigine glucuronidation. On the other ha nd, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic r ate.