Pharmacokinetics and therapeutic drug monitoring of newer antiepileptic drugs during pregnancy and the puerperium

The treatment of epilepsy in pregnancy is particularly challenging in that the fetal and maternal risks associated with maternal seizures need to be balanced against the potential teratogenic effects of antiepileptic drugs (AEDs). Pregnancy is known to affect the pharmacokinetics of older-generation AEDs. Understanding such alterations is important in the effort to optimise drug therapy since they may affect seizure control as well as fetal drug exposure. Therapeutic drug monitoring has therefore been recommended to control for changes in the disposition of the older-generation AEDs during pregnancy. Much less is known about gestation-induced alterations in the pharmacokinetics of the newer AEDs that have been introduced in the last 15 years. Lamotrigine is by far the most extensively studied of the newer AEDs. Pronounced alterations have been reported in the apparent clearance of lamotrigine, with an increase of >300% from baseline in late pregnancy in some patients on monotherapy, most likely due to enhanced metabolism. The available data suggest that the corresponding decline in plasma concentrations can be associated with loss of seizure control. More limited data indicate that a similar decline in plasma concentrations of the active monohydroxy derivative of oxcarbazepine may occur in late pregnancy. Preliminary experience also suggests that a significant fall in plasma concentrations of levetiracetam may occur during pregnancy. No systematic information is available on the pharmacokinetics during pregnancy of other newer AEDs (e.g. gabapentin, pregabalin, tiagabine, topiramate or zonisamide). Given the importance of maintaining optimal treatment of epilepsy during pregnancy, therapeutic drug monitoring appears to be justified for lamotrigine and oxcarbazepine in particular. Systematic studies of the effects of pregnancy on the pharmacokinetics of the other newer-generation AEDs are urgently needed.