Subcutaneous drug delivery: PBPK-QSP model for absorption and anti-drug antibody response

Predicting drug absorption and immunogenicity after subcutaneous administration of therapeutic proteins

15.06.2023

Graphical representation of the subcutaneous absorption and disposition model. (A) The physical injection site is represented by a volume including the injected formulation (depot in red) and the surrounding tissue organized in layers with a discrete thickness. At injection, part of the volume will form the depot while the rest, including solubilized drug, will disperse into the surrounding tissue. Spatiotemporal distribution of drug throughout the tissue is thereafter described by passive diffusion in the interstitial space. (B) Tissue organization, distribution, and description of mass transfer as implemented in PK-Sim is adopted as a physiological representation for each tissue layer. Translocation both via cell membrane permeability and endothelial fenestration may occur dependent on the molecule's properties. Moreover, generic representation of endosomal functionalities (uptake, recirculation, clearance, and neonatal Fc receptor salvaging) as well as lymphatic drainage into local and subsequent central lymph nodes are represented within each layer's interstitial space. Systemic absorption rate and bioavailability are determined by the sum of said processes.

Subcutaneous route and immunogenicity

The subcutaneous route of administration provides convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion. However, similarly to intravenous administration, there is a potential risk for undesirable effects such as anti-drug antibody emergence toward these therapeutic proteins [1].

The risk for immunogenicity can be mitigated to a certain degree by compound prioritization and tailored bioengineering [2]. Nevertheless, for subcutaneous administration, there are additional factors and challenges related to immunogenicity that may need to be considered, such as localization in tissue and aspects related to drug formulations and drug products used for this specific administration route [1,2]. Such dependencies have been observed, both in pre-clinical models and in a clinical setting, but are challenging to prospectively predict.

A two-wave mechanism of antigen presentation in the immune response toward subcutaneous proteins has been described, where interaction with dynamic antigen-presenting cells possessing high antigen processing efficiency and migratory activity is proposed to drive immunogenicity [1]. In such a biological system, several drug delivery-influenced mechanisms, such as residence time, level of aggregation, and stability, may be of direct relevance at several stages in the immunological response, from early activation of immune cells to the following immunological cascade.

Modeling approaches and project Goal

Quantitative system pharmacology (QSP) are mathematical models traditionally used to characterize biological systems, disease processes, and drug pharmacology [2]. Physiologically based biopharmaceutics (PBB) models include quantitative descriptions of a drug disposition, absorption, and bioavailability, in the organism, based on interrelationships between key physiological, biochemical, and physicochemical determinants, and the dependencies of drug delivery system, e.g., components, physical attributes, and administration route [3].

These methodologies are used, in respective scientific area, for translation and prediction to optimize chances of clinical success as well as to mitigate risks for anti-drug antibody emergence. This project aims to combine these methods by integrating the mechanisms of absorption and immune response toward therapeutic proteins administered subcutaneously while simultaneously including drug deliver-related factors of relevance for these mechanisms.

The project is co-funded by Sweden’s innovation agency (Vinnova).

Link to Vinnova website

References

Project lead / Subject matter expert

Marylore Chenel, Erik Sjögren

Related content