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

Predicting drug absorption and immunogenicity after subcutaneous administration of therapeutic proteins

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.

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

[1] Jarvi et al. BioDrugs (2021)

[2] Kierzek et a. CPT Pharmacometrics Syst. Pharmacol. (2019)

[3] Heimbach et al. The AAPS Journal (2019)