PT-001 - UTILIZING A MINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (MPBPK) MODEL FOR PREDICTING MATERNAL AND FETAL EXPOSURE TO MONOCLONAL ANTIBODIES DURING PREGNANCY

M. Kardouh¹, J. Tiley², T. Dunlap², Y. Cao²; ¹University of North Carolina at Chapel Hill and Certara, ²University of North Carolina at Chapel Hill.

Background: Monoclonal antibodies (mAbs) are widely prescribed during pregnancy to manage inflammatory and autoimmune conditions. However, there is a knowledge gap on mAbs fetal exposure and the associated risks and benefits. The neonatal Fc receptor (FcRn), expressed in the syncytiotrophoblast layer of the placenta, plays a crucial role in facilitating the placental transfer of both endogenous IgG and therapeutic mAbs. In addition, existing data, primarily derived from observational pharmacokinetic and case studies, indicate high variability in maternal and fetal exposure. The aim of this study was to develop a mPBPK model framework capable of predicting maternal and fetal exposure to mAbs throughout pregnancy.

Methods: A mPBPK model was developed including three key endosomal compartments expressing FcRn: (1) maternal vascular endothelial cells, (2) the syncytiotrophoblast cells, and (3) fetal vascular endothelial cells. The model was initially developed and validated using literature data available for the endogenous lgG. Sensitivity analyses were performed to evaluate the impact of FcRn expression variability. The developed IgG model was further optimized using infliximab (IFX) literature data and applied to predict adalimumab (ADA) and IFX levels in additional observational studies. Simulations were performed using R (version 4.2.1) and the “mrgsolve” package.

Results: The developed mPBPK model with the estimated FcRn expression variability (~30%) adequately described the maternal and fetal concentrations-time profiles of endogenous IgG throughout pregnancy. Notably, FcRn expression demonstrated an exponential increase, resulting in a rapid escalation of endogenous IgG transport to the fetus, starting at 14th week of gestation. Furthermore, the model adequately predicted maternal and fetal levels of IFX (13 patients) and ADA (10 patients) with greater than 65% of predicted median levels within two-fold range of the observed values.

Conclusion: To our knowledge, this study represents the first development of mPBPK model for describing placental transfer of endogenous IgG and therapeutic mAbs from mother to fetus throughout pregnancy. Further improvement of the model holds great promise in guiding mAbs dosing in pregnancy to ensure maternal efficacy while minimizing fetal toxicities.