Physiologically based pharmacokinetic coupled model of zonisamide to predict the exposure and dose exploration in maternal, fetal, and neonatal populations during pregnancy and postpartum

Zonisamide (ZNS) is a second-generation antiepileptic drug. During pregnancy, ZNS clearance increases, leading to a decrease in drug concentration. Additionally, ZNS can be transferred to the fetus and neonate through the mother and breast milk, potentially posing risks to the fetus and neonate. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® and MoBi® to develop a physiologically based pharmacokinetic (PBPK) coupled model predicting the exposure of ZNS in maternal, fetal, and neonatal populations during pregnancy and postpartum. The model was evaluated with clinical pharmacokinetic (PK) data, and dosage explorations were conducted. In the developed non-pregnant, pregnant, fetal, postpartum, and neonatal models, approximately 98.56 %, 95.24 %, and 100 % (fetal/postpartum/neonatal) of the observed concentrations fell within the 2-fold error range, respectively. For the first, second, and third trimesters, dose adjustments to 0.92, 1.17, and 1.5 times the baseline (the recommended maintenance dose of 300 mg QD) are the minimum effective doses (MED, exposure levels close to therapeutic drug monitoring minimum effective range of 10 µg/ml), while adjustments to 1.17, 1.5, and 1.92 times the baseline are normalized doses compared to baseline. Under the third trimester dosing regimen, postpartum dose adjustment to 1.17 times the baseline is the MED, while 1.58 times the baseline is normalized dose. Relative infant dose (RID) of neonates is 30–33 %. Immediate breastfeeding is not recommended for neonates postpartum. The ZNS PBPK coupled model was successfully developed, studying exposure in special populations during pregnancy and postpartum, and optimizing dosing regimens.