Gender Aspects of Pharmacokinetics of New and Old AEDs

Abstract

Alterations in drug disposition in pregnancy and drug transfer into breast milk during lactation are the most important gender-related aspects of the pharmacokinetics of antiepileptic drugs(AEDs). The effect of pregnancy on drug disposition has been fairly well characterized for the old AEDs. Total and unbound plasma concentrations of phenobarbital decline up to 50%. Total phenytoin levels may drop to approximately 40% of prepregnancy concentrations,but unbound concentrations considerably less. Unbound valproate levels remain unchanged despite a fairly marked decrease in total concentrations, and changes in unbound and total plasma concentrations of carbamazepine are minor. In contrast, pregnancy has a pronounced effect on lamotrigine, with a 300% increase in apparent clearance in the third trimester. Much less is known about the kinetics of other new AEDs during pregnancy. Umbilical cord/maternal plasma concentration ratios close to unity suggest free transplacental passage of most AEDs,whereas higher ratios indicate fetal accumulation of valproate and gabapentin. Milk/maternal plasma concentration ratios close to 1 demonstrate extensive transfer to breast milk of many AEDs including ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Plasma levels are, however, in general low in the nursed infant, although pharmacological concentrations have been reported occasionally for carbamazepine, ethosuximide, lamotrigine, and phenobarbital. For most of the new-generation AEDs, there is an urgent need for further kinetic data from pregnancy and breast-feeding.