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

Area of Science:

• Pharmacometrics
• Drug Metabolism and Pharmacokinetics
• Maternal-Fetal Medicine

Background:

• Lamotrigine is a widely used anti-epileptic drug in pregnancy due to low teratogenicity.
• Increased lamotrigine metabolism and clearance during pregnancy can result in suboptimal drug therapy and poor disease control.
• Proactive dosage adjustments are necessary to maintain therapeutic lamotrigine levels in pregnant individuals.

Approach:

• A systematic literature review was conducted to gather aggregate data on lamotrigine clearance in pregnancy.
• Pharmacometric modeling and simulation using PUMAS software were employed to estimate plasma concentrations across pregnancy stages.
• Simulations investigated various doses to achieve preconception-equivalent plasma concentrations above the minimum effective concentration.

Key Points:

• Simulated mean steady-state trough lamotrigine concentrations significantly decreased across trimesters (3.17 ± 0.93 mg/L, 2.14 ± 0.86 mg/L, 1.51 ± 0.65 mg/L) compared to non-pregnant women (4.31 ± 1.14 mg/L).
• Model-informed simulations suggest specific twice-daily doses (150 mg, 175 mg, 225 mg, 250 mg) for preconception and each trimester to maintain target concentrations.
• The proposed model-informed dosage regimen aims to optimize lamotrigine dosing during pregnancy.

Conclusions:

• A pharmacometric model-based framework can guide optimal lamotrigine dosage regimens in pregnancy.
• The proposed dosing strategy aims to prevent therapeutic failure by maintaining effective lamotrigine plasma concentrations.
• Therapeutic drug monitoring remains crucial to ensure the safety and efficacy of lamotrigine during pregnancy.