Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency

Abstract

Objective: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity.

Methods: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency.

Results: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52).

Conclusions: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Figure 1

Flow diagram of women enrolled in the study and information used for data analysis AED = antiepileptic drug; GTCSz = generalized tonic– clonic seizure; LTG = lamotrigine; TDM = therapeutic drug monitoring.

Figure 2

Total and free lamotrigine clearance during pregnancy Mean (± SE) total lamotrigine clearance (LTG daily dose [mg/kg]/LTG concentration [mg/L]) and mean (± SE) free lamotrigine clearance (LTG daily dose [mg/kg]/unbound LTG concentration [mg/L]) during nonpregnant baseline and each trimester of pregnancy. * p < 0.001 compared with nonpregnant baseline. δ p < 0.03 compared with first trimester. Cl = clearance.

Figure 3

Lamotrigine clearance and seizures during pregnancy and postpartum Mean (±SE) free lamotrigine clearance (LTG daily dose [mg/kg]/LTG concentration [mg/L]) and percentage of patients who had an increase in seizure frequency compared with preconception baseline, by month gestational age and month postpartum. Cl = clearance.