(M-048) Development of a whole-body physiologically-based pharmacokinetic (PBPK) model for large molecule FcRn inhibitors in pregnancy incorporating placental transfer

Sophie Fischer-Holzhausen – ESQlabs GmbH; Wilhelmus de Witte – ESQlabs GmbH; Edwin Lam – Janssen R&D, Johnson & Johnson, Spring House, PA, USA; Eleni Caratzas – Janssen R&D, Johnson & Johnson, Spring House, PA, USA; Stephan Schaller – ESQlabs GmbH; An Vermeulen – Janssen R&D, Johnson & Johnson, Beerse, Belgium; Jocelyn Leu – Janssen R&D, Johnson & Johnson, Spring House, PA, USA

Objectives: To refine a previously developed PBPK model for FcRn inhibitors by incorporating published clinical data and applying it to predict their transfer and IgG transport across the placenta in pregnancy.

Methods: The previously published extension of the large molecule model in PK-Sim [1-2] for FcRn inhibitors in mice was first applied to the human model, to obtain an FcRn inhibitor model for humans. Publicly available data from four different FcRn inhibitors (efgartigimod, rozanolixizumab, nipocalimab and batoclimab) [3-6] were used to refine the model parameters. The model parameters were simultaneously fitted for all compounds, with the compound-specific parameters being their molecular weight, FcRn affinities in the endosomal and vascular spaces and binding kinetics, and renal clearance (only for efgartigimod). This large molecule model was subsequently extended with pregnancy-related organs as described by Dalmann et al. [7,8]. The model was validated with data obtained from nipocalimab administered in pregnant individuals at high risk for Early Onset Severe Hemolytic Disease of the Fetus and Newborn (EOS-HDFN) [9,10]. Finally, FcRn-mediated transport across the placenta was implemented based on fetal endogenous IgG concentrations during pregnancy [11].

Results: The refined large molecule model for FcRn inhibitors was able to describe both the PK and the PD (i.e. endogenous IgG concentration-time profiles) of all FcRn inhibitors after optimization of two system-specific parameters (ie., the starting concentration of free FcRn, and the endosomal fraction of the vascular endothelium) and three compound-specific parameters (binding affinity to FcRn in the endosomes and in plasma, and the drug-FcRn association rate constant). The pharmacokinetics were well described for all compounds and showed a strong target-mediated drug disposition (TMDD) effect. The model was able to capture the observed increase of fetal endogenous IgG with the progression of gestational age, due to the introduction of a scaling factor, accounting for the growth of the maternal placental surface. The developed placental transfer model was applied to predict fetal drug exposure, the fetal FcRn inhibition, and the inhibition of endogenous IgG transfer from the maternal to the fetal blood circulation. Predictions showed that the FcRn inhibitors explored differed significantly in terms of fetal exposure and FcRn inhibition of maternal IgG transfer, leading to distinct fetal IgG concentration-time profiles.

Conclusions: A whole-body PBPK model capable of predicting both the PK and PD of four different FcRn inhibitors was developed for healthy non-pregnant participants. The model was extended to a pregnant women population incorporating placental transfer. The model was applied to predict fetal drug exposure, and the inhibition of FcRn-mediated transport of endogenous maternal IgG across the placenta by FcRn inhibitors. Further validation of the fetal IgG concentrations and the placental transfer model is required.

Citations: [1] Niederalt, Christoph, et al. "A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim." Journal of pharmacokinetics and pharmacodynamics 45 (2018): 235-257.
[2] de Witte, Wilhelmus EA, et al. "Mechanistic incorporation of FcRn binding in plasma and endosomes in a whole body PBPK model for large molecules." Journal of Pharmacokinetics and Pharmacodynamics 50.3 (2023): 229-241.
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[8] Dallmann, André, et al. "Applied concepts in PBPK modeling: how to extend an open systems pharmacology model to the special population of pregnant women." CPT: pharmacometrics & systems pharmacology 7.7 (2018): 419-431.
[9] Zhou, Jie, et al. “232 Nipocalimab pharmacokinetic/pharmacodynamic and exposure-response modeling in pregnancies at risk for early-onset severe (EOS) HDFN”. American Journal of Obstetrics and Gynecology vol. 230,1(2024): S138
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[11] Gill, Katherine L., and Hannah M. Jones. "Opportunities and challenges for PBPK model of mAbs in paediatrics and pregnancy." The AAPS Journal 24.4 (2022): 72.

Keywords: FcRn inhibitors, PBPK, pregnancy