Pharmacokinetics of Levetiracetam during Pregnancy, Delivery, in the Neonatal Period, and Lactation

Abstract

Summary:Purpose: To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period.Methods: Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth.Results: The umbilical cord/maternal plasma concentration ratios ranged from 0.56-2.0 (mean 1.15, n = 13). LEV plasma concentrations in the neonates declined with an estimated halflife of 18 h (n = 13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78-1.55, n = 11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p < 0.001, n = 7)Conclusions: Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

“…For example, renal clearance increases substantially during pregnancy, and small studies demonstrate that LEV levels decrease by 40 % to 62 % during the second and third trimesters [36][37][38][39]. A more detailed analysis of 12 pregnancies demonstrated an even greater change in clearance of LEV from nonpregnant baseline to the third trimester, with a mean ± SD increase from 124.7 ± 57.9 l/day to 427.3 ± 211.3 (p < 0.0001), an increase of 242 % [37]. However, the effects on seizure control are less clear from these studies.…”

Efficacy and Tolerability of Levetiracetam (Keppra®) in the Treatment of Epilepsy: Review of Literature

“…Отмечено, что этот препарат значительно проникает в грудное молоко, но большинство авторов рекомендуют не прерывать грудного вскармливания [49,50,88,95].…”

“…Леветирацетам, а также этосуксимид, вигабатрин, габапентин, прегабалин практически не связываются с белками, поэтому мож-но ожидать их поступления в грудное молоко в боль-ших количествах; и их концентрация в грудном моло-ке может быть эквивалентна концентрации в плазме матери. Однако плазменная концентрация АЭП у но-ворожденных, получающих грудное вскармливание, во всех случаях ниже ожидаемой в связи с высокими показателями элиминации [50,88,95].…”

Managing epilepsy in pregnancy

“…However, in the available literature, the clearance of levetiracetam does appear to increase significantly during pregnancy, with several studies showing a decline in serum concentration/dose ratio in the third trimester to be in the order of 50% of baseline [66,76,77].…”