Dosage Optimization of Lamotrigine in Pregnancy: A Pharmacometric Approach Using Modeling and Simulation

Lamotrigine is the most widely used anti-epileptic drug in pregnancy because of its low teratogenicity. However, there is an increased metabolism and clearance of lamotrigine in pregnancy contributing to suboptimal drug therapy and poor disease control, prompting the need for proactive dosage adjustments. The present study aimed to develop a pharmacometric model-based framework for recommending an optimal dosage regimen for lamotrigine in pregnancy. A systematic review was performed to obtain aggregate data from the literature on the clearance of lamotrigine in pregnancy. The data were incorporated into simulations using PUMAS software to estimate the plasma concentrations at the preconception stage and during the 3 trimesters of pregnancy. Simulated drug exposures for different doses were investigated to ascertain plasma concentrations similar to the preconception value and above the minimum effective concentration. The simulated mean steady-state trough plasma concentrations of lamotrigine were significantly decreased in pregnant women over the course of the 3 trimesters (3.17 ± 0.93 mg/L, 2.14 ± 0.86 mg/L, and 1.51 ± 0.65 mg/L, respectively), compared with non-pregnant women (4.31 ± 1.14 mg/L) (P < .001). The simulation studies revealed that doses of 150 mg, 175 mg, 225 mg, and 250 mg twice daily in the preconception stage and the 3 trimesters, respectively, achieve the target concentrations. Thus, the model-informed dosage regimen of lamotrigine proposed in this study shall be used to initiate appropriate dosing in pregnant women; however, the safety and efficacy of the drug must be assured through therapeutic drug monitoring in order to avoid therapeutic failure of lamotrigine in pregnancy.