Clinical Pharmacokinetics of Antiepileptic Drugs in Paediatric Patients

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.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…The clearance of 10-hydroxycarbazepine is increased in pregnancy [126] and in patients taking liver enzyme-inducing drugs [38]. Young children require higher doses of oxcarbazepine per body weight than adults [127]. …”

Unusual presentation of iatrogenic phenytoin toxicity in a newborn

“…The biotransformation of phenytoin to its major hydroxylated metabolite is saturable at plasma concentrations Ͼ 5 mg/L giving rise to a non-linear dose-serum concentration relationship [9]. In neonates and infants to 3 months of age, the free fraction of phenytoin in plasma may be significantly increased (i.e., 10 to 15 %) over that observed in healthy young adults (e.g., free fraction of 2 to 5 %) [10].…”

Clinical Drug Development in Epilepsy Revisited: A Proposal for a New Paradigm Streamlined Using Extrapolation

“…Extrapolation of efficacy data from adults or older paediatric patients to these groups is not possible because of differences in the pathophysiology of the epilepsy as well as brain biochemistry, brain development and drug metabolism. Drug clearance is low in preterm and term newborn infants, subsequently increases rapidly until around 2 years and then declines steadily until around 12 years at which point it is considered to have reached adult levels, such that adult dosing can be considered for adolescents aged >12 years [15]; this is well-illustrated by carbamazepine [16]. However, sufficient variability exists that pharmacokinetic studies are likely to be required to support dose choices for paediatric patients aged 2–12 years even when efficacy is extrapolated.…”