Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetic Changes of Topiramate During Pregnancy and Recommend Dose Adjustments

Abstract Topiramate is increasingly used in the treatment of epilepsy during pregnancy. However, its plasma concentration evidently decreases during pregnancy, which may reduce its efficacy. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of topiramate to simulate maternal and fetal pharmacokinetic changes across different trimesters and to propose dose adjustments. We established a topiramate pregnancy PBPK model in PK‐Sim and Mobi. The model was validated using clinically observed data and subsequently used to optimize the dosage during pregnancy. Simulation results showed that the mean steady‐state trough plasma concentration of topiramate decreased by 9.4%, 32%, and 46% in the first, second, and third trimesters, respectively. Based on these findings, the dosage should remain unchanged during the first trimester of pregnancy. However, increasing the baseline dose of topiramate by at least 1.5‐ and 1.9‐fold during the second and third trimesters, respectively, may help maintain effective plasma concentrations. This study provides reference information for topiramate dosage adjustment during pregnancy and helps improve its safety and efficacy in pregnant women and fetuses.