(W0930-10-65) Bioavailability and Local Immunogenicity after Subcutaneous Administration of Therapeutic Proteins: Mechanistic Modelling within the Open Systems Pharmacology Framework

Purpose: The subcutaneous (SC) route of administration is frequently used to deliver therapeutic proteins (TPs). However, the systemic bioavailability of TPs when given SC is often incomplete, which can significantly reduce the systemic exposure and therapeutic efficacy [1]. Local proteolysis in lysosomes at the site of injection can mediate pre-systemic degradation. Similarly, local resident and, upon stimuli of the injection, migrating immune cells could expediate both first-pass degradation and a signal to immunogenetic response with injection dependent consequences for the systemic immunogenicity [2]. These two elements were incorporated into a previously described mechanistic absorption and systemic immunogenicity PBPK-QSP model implemented and harmonized to the Open Systems Pharmacology (OSP) framework, to allow for more informed predictions of the pharmacokinetics and immunogenicity of TP following SC administration [3]. The presented work aims to: 1) implement mechanisms of size dependent extravasation, according to the 2-pore formalism, in the mechanistic model framework for subcutaneous (SC) administration; 2) introduce local endosomal uptake, degradation, endothelial trafficking, and neonatal Fc receptor(FcRn) salvaging according to the generic implementation in PK-Sim; 3) develop a QSP model for local SC immune cell activity and response upon injection based on preclinical observations; 4) integrate established local SC immunogenicity and absorption model with systemic pharmacokinetics and immunogenicity within the OSP framework. 5) evaluate implementations in terms of bioavailability and immunogenicity.

Methods: All activities were performed within MoBi and aligning to implementations in PK-Sim to allow for full integration in the Open Systems Pharmacology framework [4]. Previously described models for local distribution and absorption after SC administration and systemic immunogenicity was used as starting point [3,5]. Implementation of the generic distribution model of TPs in PK-Sim was incorporated in the SC absorption model to accommodate for local endosomal uptake, degradation, endothelial trafficking, and FcRn salvaging. Evaluation of this implementation was conducted within a range of molecular sizes and FcRn affinities of TPs reported in literature [7].

Results: The model predicted size dependent retention and reduced systemic appearance rate with increased molecular size. First pass elimination via endosomal degradation increased because of increased retention while it was significantly reduced by FcRn salvaging. For a typical mAb (150 kDa) the predicted time to complete absorption was ~ 4-6 days, dependent of FcRn salvaging, and the bioavailability was >90% and < 80% with (Kd_FcRn< =1 µM) and without (Kd_FcRn>1 µM) FcRn salvaging, respectively (Figure 1). The model for local immune cell dynamics increased the systemic immunogenicity response dependent on molecular size and epitope potency with effects on systemic PK after SC drug administration (Figure 2). This effect was mediated by downstream effects on immune cell differentiation and memory cell pool.

Conclusion: In conclusion, our open-source platform for modelling SC administration in the Open Systems Pharmacology framework was further developed with mechanistic descriptions. The results demonstrated how the model platform could aid drug development through multi-layered analysis including drug absorption, bioavailability, and exposure as well as immunogenic response. This provides a valuable tool for predictions of exposure and efficacy of TP after SC administration including the possibility to assess immunogenicity consequences of switching from intravenous to SC route of administration.

References: [1] Porter, CJ., Charman, SA. (2000) Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 89(3):297–310.
[2] Varkhede. N., Bommana. R., Schöneich. C., Forrest. ML., (2020) Proteolysis and oxidation of therapeutic proteins after intradermal or subcutaneous administration. J Pharm Sci. 109(1):191-205.
[3] Moriah Pellowe. M., Eriksson. J., Chenel. M., Sjögren. E., (2022) A platform for mechanistic modelling of subcutaneous administration with the effect of immunogenicity within the Open Systems Pharmacology framework. PAGE meeting, Ljubljana, Slovenia
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[5] Chen, X., Hickling, T. P., & Vicini, P. (2014). A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins: part 1—theoretical model. CPT: pharmacometrics & systems pharmacology, 3(9), 1-9.
[6] Chen, X., Hickling, T. P., & Vicini, P. (2014). A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins: part 2—model applications. CPT: pharmacometrics & systems pharmacology, 3(9), 1-10.
[7] Niederalt. C., Kuepfer. L., Solodenko. J., Eissing. T., Siegmund. HU., Block. M., Willmann. S., Lippert. J. (2018) A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. J Pharmacokinet Pharmacodyn 45(2):235-257
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[9] Liang, F. et al. (2017). Efficient Targeting and Activation of Antigen-Presenting Cells In Vivo after Modified mRNA Vaccine Administration in Rhesus Macaques. Mol. Ther. 25, 2635–2647

Acknowledgements: The presented work was carried out with support from Sweden´s Innovation Agency.

Subcutaneous absorption and bioavailability. Cumulative fraction of dose leaving the injection site for systemic absorption after SC administration (1 µmol) of generic therapeutic proteins (150 kDa) with different affinity (µM) to the neonatal Fc receptor.

Subcutaneous immune cell dynamics and immune response. a) Observed (dots) and model fitted curves of the dynamic immune cell response to mRNA loaded lipid nanoparticles (LNP) after intradermal injection in non-human primates. b) Model simulated immunogenic response, visualized as formation of anti-drug antibodies (ADA) over time, of two different sizes antigen, 50 kDa (blue) and 150 kDa (Orange), and epitope binding affinities, 1 nM (solid) and 100 nM (dashed).