Antiepileptic drug pharmacokinetics during pregnancy and lactation

The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic 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. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited studies of the newer AEDs indicate similar extensive transplacental transfer [LTG, oxcarbazepine, topiramate (TPM), zonisamide (ZNS)], and breast milk/maternal plasma concentration ratios less than 1 (LTG, TPM, ZNS). Especially high excretion of levetiracetam into breast milk may occur. Current published guidelines recommend that the ideal AED concentration should be established for each patient before conception and that monitoring of AED concentrations should be performed during each trimester and in the last month of pregnancy. Free concentrations should be measured for phenobarbital, phenytoin, carbamazepine, valproic acid, and primidone. Some authors recommend at least monthly monitoring of AED concentrations, especially for LTG. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy and the postpartum period could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but, at the same time, to minimize fetal drug exposure.