CLINICAL PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS IN PEDIATRIC-PATIENTS .2. PHENYTOIN, CARBAMAZEPINE, SULTHIAME, LAMOTRIGINE, VIGABATRIN, OXCARBAZEPINE AND FELBAMATE

This article is the second part of a review of the pharmacokinetics of antiepileptic drugs (AEDs) in paediatric patients, It reviews 139 pap ers published since 1969 on the pharmacokinetics of phenytoin, carbama zepine, sulthiame, lamotrigine (phenyltriazine), vigabatrin, oxcarbaze pine and felbamate in this population. The pharmacokinetics of phenyto in are significantly affected by age, The terminal elimination half-li fe (t1/2z) is relatively long in neonates; it then decreases during th e first postnatal month to lower values than in adults, and then progr essively increases with age due to an age-dependent decrease in the me tabolic rate. Rate of elimination is strongly dose-dependent at all ag es. The combination of these factors makes it difficult to predict wha t plasma concentrations would result from dose per kilogram (dose/kg) adjustments in neonates and children, especially when phenytoin is coa dministered with other liver enzyme-inducing drugs, such as phenobarbi tal and carbamazepine. The concentration of phenytoin in brain and oth er tissues depends on the unbound/total concentration ratio. For neona tes this ratio is higher than that found in adults; it then decreases over the first 3 postnatal months to approach adult values. The fracti on of unbound phenytoin is significantly higher in patients also recei ving valproic acid. Carbamazepine is almost completely epoxidised to t he active metabolite carbamazepine epoxide, which is in turn converted to carbamazepine diol. Metabolic conversion of carbamazepine and rena l clearance of carbamazepine diol are much higher in children than in adults; t1/2z of carbamazepine is thus very short in young children, t han increasing with age. Nn data are available on the neonatal period. The carbamazepine epoxide/carbamazepine ratio may be significantly in creased by metabolic inducers (e.g. phenytoin, phenobarbital and primi done) or by inhibitors of the carbamazepine epoxide to carbamazepine d iol conversion (e.g. valproic acid). Macrolides inhibit carbamazepine metabolism, thus increasing carbamazepine plasma concentrations. Drug- induced changes in carbamazepine kinetics are particularly pronounced in children. In children, a higher dose/kg of sulthiame, lamotrigine, oxcarbazepine and felbamate than in adults is required to obtain an ef fective plasma concentration. The published data do not support the us e of a different dose/kg of vigabatrin in children aged between 1 mont h and 15 years. The pharmacokinetic information in the paediatric lite rature may help in assessing AED prescriptions in childhood to prevent seizures and AED-related adverse effects on the ongoing maturational processes of the brain.