Authors :
Presenting Author: Yuhan Long, BS, BSChE – University of Minnesota
Page Pennell, MD – University of Pittsburgh; Kimford Meador, MD – Stanford University; Ashwin Karanam, PhD – University of Minnesota; Paula Voinescu, MD – Harvard University; Angela Birnbaum, PhD – University of Minnesota
Rationale: Two populations of women have been identified that exhibit differences in the magnitude of lamotrigine clearance changes during pregnancy. Hormone concentrations also change throughout pregnancy with a strong correlation between lamotrigine and estradiol concentrations. Our objective was to characterize estradiol, estrone, and progesterone concentrations during pregnancy in the two clearance populations (low versus high) of women with epilepsy on lamotrigine.
Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) is a 20-site prospective, observational cohort study. Pregnant women with epilepsy enrolled participated for a total of seven visits. Estradiol, estrone, and progesterone were collected along with antiseizure medication concentrations. A population mixed-effects modeling approach was used to characterize lamotrigine pharmacokinetics and identify if a woman was in the low or high clearance subpopulation based on lamotrigine clearance based on a previous model (Polepally et. al., Annals of Clinical and Translational Neurology, 2014). Linear models were developed for estrone, estradiol, and progesterone, as well as progesterone to estradiol ratio versus gestational age with clearance subpopulation as an additional predictor variable. To test for differences in hormonal change between the subpopulations in each model, slopes between subpopulations were compared using t-tests. The cutoff of statistical significance was set at α = 0.05.
Results: There were 351 concentrations for estrone, estradiol, and progesterone each from 109 pregnant women with epilepsy. For the high clearance (n=99; 314 concentrations) and low clearance (n=10; 39 concentrations) subgroups on average, estrone increased at a rate of 200.1 and 152.6 pg/mL per week, respectively; estradiol increased at a rate of 479.3 and 405.6 pg/mL per week; and progesterone increased at a rate of 3.70 and 3.58 ng/mL per week during pregnancy. There was no statistical difference found between the slopes or intercepts of subpopulations for estrone (p = 0.471), estradiol (p = 0.432), or progesterone (p = 0.872). Gestational age was found to be a significant predictor of estrone (p < 0.001), estradiol (p < 0.001), and progesterone (p < 0.001) changes. For the progesterone/estradiol model, the ratio decreased by 0.000054 per week (p < 0.001) with no significant difference between the two subpopulations (p = 0.759).