Prenatal diagnosis · 2026
Sotalol Dose Optimization for Fetal Tachycardia: A Pregnancy Physiologically Based Pharmacokinetic Model Study.
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van Hove Hedwig, van der Heijden Joyce E M, van Uden Anne, Gijsen Violette M G J, Greupink Rick, de Wildt Saskia N, van Drongelen Joris
Аннотация
OBJECTIVE: To establish an optimized sotalol dosing strategy for fetal tachycardia using a pregnancy physiologically based pharmacokinetic (PBPK) model.
METHOD: A verified PBPK model was developed incorporating pregnancy-induced physiological changes and placental transfer. Simulations were performed to evaluate current dosing recommendations and alternative dosing scenarios were explored. To avoid maternal dose-related toxicity (QT-prolongation), we aimed for maternal concentrations < 2.5 mg/L. Based on neonatal concentration-effect data, we aimed for fetal Ctrough concentrations of 0.4-1.0 mg/L.
RESULTS: Model predictions for maternal and fetal plasma concentrations were generally consistent with available maternal and fetal exposure data. Simulations showed that at the maximum oral daily dose of 480 mg, 16% of maternal concentrations exceeded the toxicity threshold, while 90% of fetuses had therapeutic Ctrough levels. Reducing the daily dose to 400 mg lowered maternal overexposure to 0.1%, with 87% of fetuses still reaching therapeutic levels. Additionally, splitting the 480 mg dose into three administrations per day reduced maternal overexposure to 0.3% and increased fetal target attainment to 95%.
CONCLUSION: Pregnancy PBPK modeling is a valuable tool for optimizing fetal sotalol therapy. A daily dose not exceeding 400 mg, or dividing daily doses of 240 mg and higher into three administrations, may optimize the balance between predicted fetal efficacy and maternal toxicity risk.
METHOD: A verified PBPK model was developed incorporating pregnancy-induced physiological changes and placental transfer. Simulations were performed to evaluate current dosing recommendations and alternative dosing scenarios were explored. To avoid maternal dose-related toxicity (QT-prolongation), we aimed for maternal concentrations < 2.5 mg/L. Based on neonatal concentration-effect data, we aimed for fetal Ctrough concentrations of 0.4-1.0 mg/L.
RESULTS: Model predictions for maternal and fetal plasma concentrations were generally consistent with available maternal and fetal exposure data. Simulations showed that at the maximum oral daily dose of 480 mg, 16% of maternal concentrations exceeded the toxicity threshold, while 90% of fetuses had therapeutic Ctrough levels. Reducing the daily dose to 400 mg lowered maternal overexposure to 0.1%, with 87% of fetuses still reaching therapeutic levels. Additionally, splitting the 480 mg dose into three administrations per day reduced maternal overexposure to 0.3% and increased fetal target attainment to 95%.
CONCLUSION: Pregnancy PBPK modeling is a valuable tool for optimizing fetal sotalol therapy. A daily dose not exceeding 400 mg, or dividing daily doses of 240 mg and higher into three administrations, may optimize the balance between predicted fetal efficacy and maternal toxicity risk.