Toward Precision Dosing of Lamotrigine During Pregnancy: Physiologically Based Pharmacokinetic Modeling and Simulation.

Abstract

Lamotrigine is a commonly used anti-seizure medication in pregnant women. However, its pharmacokinetics (PK) during pregnancy markedly change, increasing the frequency of seizures and endangering the safety of the mother and fetus. Meanwhile, insufficient PK data on lamotrigine during pregnancy hinders its dose adjustment. This study aimed to predict the maternal and fetal PK of lamotrigine and provide recommendations for dose adjustment. A physiologically based pharmacokinetic (PBPK) model of lamotrigine was constructed using PK-Sim and MoBi and validated with clinical data. The area under the steady-state concentration-time curve (AUC) for lamotrigine decreased by 66.5%, 71.1%, and 81.2% during early, mid, and late pregnancy, respectively, compared with non-pregnant conditions. To achieve effective exposure, three, three, and five times the baseline dose were recommended during early, mid, and late pregnancy, respectively. The fetal PK was best predicted using the isolated cotyledon perfusion method compared to the Caco-2 cell permeability and MoBi default methods. Based on the fetal risk concentration (4.87 mg/L), during early, mid, and late pregnancy, the maximum recommended once-daily dosage should not exceed 400, 500, and 700 mg, respectively, and the twice-daily dosage should not exceed 300, 400, and 600 mg, respectively. The significant decrease in lamotrigine exposure may increase the frequency of seizures in pregnant women. Therefore, prompt dose adjustment is recommended to control seizures while ensuring fetal safety.