Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Abstract

Drug transport and uptake in the subcutaneous tissue receives increasing attention in biomechanical and pharmaceutical researches, as subcutaneous administration becomes a common approach for the delivery of biotherapeutics, such as monoclonal antibodies. In this paper, high-fidelity numerical simulations are used to investigate the mechanisms governing drug transport and absorption in the subcutaneous tissue, which is expressed as a porous medium modeled by Darcy's law. The effects of tissue properties (permeability and porosity), the injection flow rate, and the vascular permeability of lymphatic vessels on the lymphatic uptake are studied. Additionally, an empirical formula for the lymphatic uptake during the injection is developed based on the numerical results. The roles of lymphatic drainage, blood perfusion, osmotic pressure, and the drug binding to the cells and the extracellular matrix in the lymphatic uptake are systematically studied. Furthermore, the drug distribution and absorption in a multi-layered porous medium are investigated to illustrate the effect of heterogeneity of permeability, as the permeability varies over a wide range in different layers of the tissue (such as dermis, subcutaneous tissue, muscle). While the interstitial pressure plays an essential role in the mechanisms regulating the absorption of free monoclonal antibodies, the binding and metabolism of drug proteins also affect the drug absorption by reducing the total free monoclonal antibodies.