Yujie Yang 1, Zhimin Li 2, Yong Yang 2
1 College of Medicine, Southwest Jiaotong University,The Third People's Hospital of Chengdu, (Chengdu, China), 2 Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China (Chengdu, China)
Introduction: Cyclosporine A (CsA) is increasingly being used in reproductive medicine and pregnancy immunotherapy. However, pregnancy-induced physiological changes may substantially alter the pharmacokinetics of CsA.
Objectives: This study aimed to characterize maternal and fetal exposure to CsA during pregnancy using a physiologically based pharmacokinetic (PBPK) modeling approach.
Methods: A whole-body PBPK model for CsA was developed by PK-Sim®. The model was validated using clinically observed data and subsequently extrapolated to pregnant women by incorporating gestational age–dependent physiological changes using the Mobi®. A maternal–fetal PBPK framework was constructed to describe CsA disposition in the mother, placenta, and fetus. Maternal and fetal CsA exposure profiles were simulated across different gestational stages.
Results: The PBPK model adequately described CsA whole blood concentration–time profiles in non-pregnant adults and successfully extrapolated it to the pregnant population, wherein the MFE average and GMFE of all predicted PK parameters were within a 1.5-fold error range. CsA was predicted to cross the placenta, the fetal-to-maternal concentration ratio were 0.36, 0.23, and 0.22 for the first, second, and third trimesters, respectively. Sensitivity analyses identified the first-pass metabolic capacity of CYP3A4 in liver during pregnancy is a key regulator of maternal and fetal drug exposure. The simulation indicated that for the first, second, and third trimesters, dose recommended to 2.5, 3.5, and 4 mg/kg are the maximal effective dose.
Conclusion: This study provides a mechanistic, quantitative description of CsA pharmacokinetics during pregnancy and offers insights into fetal drug exposure. Maternal–fetal PBPK modeling provides a reference for realizing clinical personalized medication for pregnant women.
Reference: PAGE 34 (2026) Abstr 12099 [www.page-meeting.org/?abstract=12099]
Poster: Drug/Disease Modelling - Safety