Characterization of lamotrigine disposition changes during and after pregnancy in women with epilepsy

Background: Lamotrigine clearance can change drastically in pregnant women with epilepsy (PWWE) making it difficult to assess the need for dosing adjustments. Our objective was to characterize lamotrigine pharmacokinetics in PWWE during pregnancy and postpartum along with a control group of nonpregnant women with epilepsy (NPWWE). Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study was a prospective, observational, 20 site, cohort study conducted in the United States (December 2012 and February 2016). Inclusion criteria included patients aged 14-45 years, gestational age <20 weeks at the time of recruitment, IQ >70 points, and receiving lamotrigine. PWWE participated throughout pregnancy and 18 months postpartum with NPWWE having matched visit intervals. Plasma drug and hormone concentrations were measured at each of the seven visits. A population mixed-effects modeling approach was used to describe lamotrigine clearance change. Results: 221 (170 PWWE, 51 NPWWE) women were included. Baseline apparent clearance (clearance for NPWWE and when not pregnant for PWWE) was identical between the two groups (2.79 L/hour. with 36% between-subject variability). Two subpopulations were identified in PWWE: similar to 91% of PWWE had a maximum increase to 275% of baseline clearance with 50% of the maximum increase reached at 12 weeks gestational age and similar to 9% had no significant change in clearance during gestation. Following delivery, a first-order mono-exponential decline (1.27 weeks-1) in clearance as a function of postpartum week described a return of clearance to baseline. The use of estrogen-based medication and enzyme-inducing antiseizure medications increased nonpregnant clearance by a further 0.33-fold and 0.84-fold, respectively. Discussion: During pregnancy, 91% of PWWE experience a 275% change from nonpregnant baseline in lamotrigine clearance whereas the remaining PWWE experience little to no change. Nonpregnant baseline lamotrigine clearance was higher in both PWWE and NPWWE with the administration of oral estrogen-containing medications. Our results are of clinical importance as they indicate a subpopulation without the need for substantial dose changes during pregnancy and a source of potential difference across nonpregnant individuals.