Antiepileptic drug therapy in pregnancy I: gestation-induced effects on AED pharmacokinetics

The ideal management of women with epilepsy during pregnancy involves achieving an optimal balance between minimizing fetal exposure to the deleterious influences of both antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiological changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Many of the AEDs are characterized by significant increases in clearance during pregnancy. Studies performed thus far provide convincing findings for significant increases in the clearance of lamotrigine and phenytoin during pregnancy; other studies support that phenobarbital, oxcarbazepine, and levetiracetam clearances also most likely increase during pregnancy. Therapeutic drug monitoring of lamotrigine with adjustment of dosages during pregnancy to maintain that individual's target concentration has been shown to decrease the risk for increased seizure frequency. Reports of seizure worsening with decreased concentrations of other AEDs have been reported but not studied in similar formal protocols. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy, with assessment of maternal and fetal/newborn consequences, could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but at the same time minimize fetal drug exposure.