Physiologically based pharmacokinetic integrated models for lamotrigine to evaluate drug exposure and optimize dosage during pregnancy, foetal period, postpartum period, and in breastfed neonates

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AIM: This study aims to develop an integrated physiologically based pharmacokinetic (PBPK) model for lamotrigine (LTG) to evaluate drug exposure during pregnancy, the postpartum, and while breastfeeding neonates, as well as to optimize dosing regimens. This study also aims to maintain maternal seizure control while minimizing neonatal risks. METHODS: Integrated PBPK model was built using PK-Sim® and MoBi®. Published plasma concentration-time profiles were digitized, and parameters were optimized via Monte Carlo algorithm. Each model's accuracy was validated against clinical PK data, using fold error (0.5-2), average fold error (AFE ≈ 1) and absolute average fold error (AAFE <1.5) as metrics for model stability and acceptability. RESULTS: Integrated PBPK model showed good accuracy and stability (non-pregnant: AFE 0.99, AAFE 1.19; pregnant: AFE 1.12, AAFE 1.34; postpartum: AFE 1.05, AAFE 1.15; lactation: AFE 1.08, AAFE 1.24; neonatal: AFE 0.95, AAFE 1.33). Simulations indicated that during pregnancy, the original LTG dose required increases of 1.3-, 2.4- and 2.7-fold in the first, second and third trimesters, respectively, to achieve the target concentration ratio, and by 2-, 4- and 4.2-fold to reach pre-pregnancy levels. Postpartum, reducing the dose by 25% weekly for 3 weeks enabled a stable return to pre-pregnancy exposure. When the postpartum LTG dose exceeded 300 mg/day, closer attention was needed for neonates aged 0-4 weeks. CONCLUSION: The developed PBPK model successfully simulated LTG exposure throughout pregnancy, the postpartum period and lactation. It also provided recommendations regarding dose optimization and safety.