Summary:Purpose: To investigate the pharmacokinetics of lamotrigine (LTG) during delivery, during the neonatal period, and lactation.Methods: High-performance liquid chromatography was used to determine plasma and milk levels of LTG in nine pregnant women with epilepsy treated with LTG, and plasma levels in their 10 infants. Samples were obtained at delivery, the first 3 days postpartum, and at breast-feeding 2-3 weeks after delivery.Results: At delivery, maternal plasma LTG concentrations were similar to those from the umbilical cord, indicating extensive placenlal transfer of LTG. There was a slow decline in the LTG plasma concentration in the newborn. At 72 h postpartum, median LTG plasma levels in the infants were 75% of the cord plasma levels (range, 50-100%). The median milk/ maternal plasma concentration ratio was 0.61 (range, 0.47-0.77) 2-3 weeks after delivery, and the nursed infants maintained LTG plasma concentrations of -30% (median, range 23-50%) of the mother's plasma levels. Maternal plasma LTG concentrations increased significantly during the first 2 weeks after parturition, the median increase in plasma concentration/ dose ratio being 170%.Conclusions: Our data demonstrate a marked change in maternal LTG kinetics after delivery, possibly reflecting a normalization of an induced metabolism of LTG during pregnancy. LTG is excreted in considerable amounts in breast milk (the dose to the infant can be estimated to 20.2-1 mg/kg/day 2-3 weeks postpartum), which in combination with a slow elimination in the infants, may result in LTG plasma concentrations comparable to what is reported during active LTG therapy. No adverse effects were observed in the infants, however. Key Words: Epilepsy-Pregnancy-LamotriginePharmacokinetics-Breast milk.Lamotrigine (LTG) is a widely used antiepileptic drug (AED) currently available in -70 countries. With a more widespread use of the drug, an increasing number of women will be exposed to LTG during pregnancy and lactation. An International Lamotrigine Pregnancy Registry has been set up by the manufacturer to collect information about pregnant women exposed to LTG (1). As of March 31, 1999, 167 pregnancies with LTG exposure had been prospectively included. The registry is focusing on pregnancy outcome in terms of birth defects. However, most women who take AEDs during pregnancy continue to do so after delivery. The drugs may thus affect the child, not only in the form of birth defects induced in early fetal life, but also through pharmacologic effects later in pregnancy, after delivery, and during lactation. It is for this reason important to obtain Accepted January 26, 2000. Address correspondence and reprint requests to Dr. I. Ohman at Department of Clinical Pharmacology, Karolinska Hospital, S-171 76 Stockholm, Sweden, E-mai1:inoeh 63 mb.ks.se information on transfer of the drug over the placenta, on the capacity of the newborn to eliminate the drug, and on the exposure of the infant to the drug through breastfeeding.LTG is a phenyltriazine AED structurally unrelated...

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.

The mean steady-state plasma concentration of lamotrigine (LTG) was 13 micro mol/L in 22 women taking LTG in combination oral contraceptives (OC) compared with 28 micro mol/L among 30 women on LTG who did not take OC (p < 0.0001). The LTG dose/body weight/plasma concentration was 2.1 L/kg/day in women on OC compared with 0.8 L/kg/day in women without OC (p < 0.0001), indicating that LTG plasma levels are reduced by >50% during OC co-medication. It is advisable to monitor LTG plasma levels in conjunction with initiation or withdrawal of OC in women on LTG therapy.

Summary:Purpose: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebocontrolled, crossover study in patients with epilepsy.Methods: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill.Results: The mean dose-corrected LTG concentration after placebo treatment was 84% [95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, −20-61%) when shifting from oral contraceptives to placebo.Conclusions: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).

SUMMARYObjective: To further characterize pregnancyinduced alterations in the pharmacokinetics of lamotrigine (LTG). Methods: Fifteen women treated with LTG were studied during 17 pregnancies. Complete trough blood samples from all trimesters and baseline > 1 month after delivery were available for 12 pregnancies (Group A), whereas, five contributed with samples only from the third trimester and baseline (Group B). High-performance liquid chromatography (HPLC) was used to determine LTG plasma concentrations, and liquid chromatography-mass spectrometry to assay the main metabolite 2-Nlamotrigine glucuronide (2-N-GLUC) in plasma. Results: In group A, the mean dose/plasma concentration ratio (D/C) of LTG at baseline after pregnancy was 66.5 ± 17.9 (± SD) L/day and approximately 250% higher in late pregnancy. The mean lamotrigine-2-N-glucuronide/lamotrigine plasma concentration ratio (2-N-GLUC/LTG) was 0.349 ± 0.141 (± SD) at baseline and 147% higher in late pregnancy. Taking group A and B together, the 2-N-GLUC/LTG ratio was 175% higher in the third trimester compared to baseline. Conclusion: Our study confirms a significant decline in LTG plasma levels during pregnancy in women on monotherapy with LTG. An increased 2-N-GLUC/LTG ratio suggests that this decline may be related to an increased metabolism of LTG by glucuronidation.