Subcutaneous absorption of biotherapeutics: knowns and unknowns

Subcutaneous administration of biotherapeutics offers several potential advantages compared with intravenous administration. Many biotherapeutics, both marketed or in development, are administered via the subcutaneous route. This minireview provides an overview of the presystemic absorption processes following subcutaneous administration, the resulting pharmacokinetics after subcutaneous administration, and provides recent case examples of the development of subcutaneous administered drugs with a focus on monoclonal antibodies. Subcutaneous absorption of biotherapeutics is relatively slow and mostly incomplete. Knowledge of the subcutaneous tissue is important to understand the absorption kinetics after subcutaneous administration. Transport in the subcutis to the absorbing blood or lymph capillaries appears to be a major contributor to the slow subcutaneous absorption. Larger proteins (>20 kDa) are mostly absorbed via the lymphatic system, although potential species differences are not fully understood yet. Also, the presystemic catabolism leading to incomplete bioavailability is little understood, both the involved enzymes and its translation across species. For IgGs, binding to the neonatal Fc receptor is important to obtain a high bioavailability. Overall, several aspects of subcutaneous absorption are still poorly understood, which hampers, e.g., translation across species. Further research in this area is warranted.