Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate

Abstract

This article is the second part of a review of the pharmacokinetics of antiepileptic drugs (AEDs) in paediatric patients. It reviews 139 papers published since 1969 on the pharmacokinetics of phenytoin, carbamazepine, sulthiame, lamotrigine (phenyltriazine), vigabatrin, oxcarbazepine and felbamate in this population. The pharmacokinetics of phenytoin are significantly affected by age. The terminal elimination half-life (t1/2z) is relatively long in neonates; it then decreases during the first postnatal month to lower values than in adults, and then progressively increases with age due to an age-dependent decrease in the metabolic rate. Rate of elimination is strongly dose-dependent at all ages. The combination of these factors makes it difficult to predict what plasma concentrations would result from dose per kilogram (dose/kg) adjustments in neonates and children, especially when phenytoin is coadministered with other liver enzyme-inducing drugs, such as phenobarbital and carbamazepine. The concentration of phenytoin in brain and other tissues depends on the unbound/total concentration ratio. For neonates this ratio is higher than that found in adults; it then decreases over the first 3 postnatal months to approach adult values. The fraction of unbound phenytoin is significantly higher in patients also receiving valproic acid. Carbamazepine is almost completely epoxidised to the active metabolite carbamazepine epoxide, which is in turn converted to carbamazepine diol. Metabolic conversion of carbamazepine and renal clearance of carbamazepine diol are much higher in children than in adults; t1/2z of carbamazepine is thus very short in young children, increasing with age. No data are available on the neonatal period. The carbamazepine epoxide/carbamazepine ratio may be significantly increased by metabolic inducers (e.g. phenytoin, phenobarbital and primidone) or by inhibitors of the carbamazepine epoxide to carbamazepine diol 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 effective plasma concentration. The published data do not support the use of a different dose/kg of vigabatrin in children age between 1 month and 15 years. The pharmacokinetic information in the paediatric literature may help in assessing AED prescriptions in childhood to prevent seizures and AED-related adverse effects on the ongoing maturational processes of the brain.