Physiological based pharmacokinetic and biopharmaceutics modelling of subcutaneously administered compounds - An overview of in silico models

Subcutaneous injection is a commonly used route of drug administration for both small molecules and biologics. To facilitate the development of new subcutaneously administered drugs, methods for prediction of drug absorption from the injection site are essential. For this purpose, in silico models have increasingly been used. This report summarize the current state of in silico models for description and prediction of subcutaneous drug absorption. Original articles on physiologically based models describing subcutaneous administration published from 2010 and onward were reviewed. Eighteen physiologically based models were identified: eleven for small molecules and seven for biologics. Most models described the PK of one drug and for one species. In models for small molecules, the subcutaneous administration site was most often described as a depot compartment with first-order absorption into the plasma or blood. Most models for biologics divided administration and organ compartments into vascular and interstitial subcompartments. Mass transfer to these compartments was frequently described with convection and diffusion, according to the one- or two-pore theory. Tremendous improvement in the quantitative aspects of subcutaneous administration and subsequent absorption of physiologically based models has occurred the last decade. However, improvements related to data translation and generalization of these models were identified.