Multiphysics Simulation of Local Transport and Absorption Coupled with Pharmacokinetic Modeling of Systemic Exposure of Subcutaneously Injected Drug Solution.

introductionSubcutaneous (SC) injectables have become more acceptable and feasible for administration of biologics and small molecules. However, efficient development of these products is limited to costly and time-consuming techniques, partially because absorption mechanisms and kinetics at the local site of injection remain poorly understood.

objectiveTo bridge formulation critical quality attributes (CQA) of injectables with local physiological conditions to predict systemic exposure of these products. METHODOLOGY: We have previously developed a multiscale, multiphysics computational model to simulate lymphatic absorption and whole-body pharmacokinetics of monoclonal antibodies. The same simulation framework was applied in this study to compute the capillary absorption of solubilized small molecule drugs that are injected subcutaneously. Sensitivity analyses were conducted to probe the impact by key simulation parameters on the local and systemic exposures.

resultsThis framework was capable of determining which parameters had the biggest impact on small molecule absorption in the SC. Particularly, membrane permeability of a drug was found to have the biggest impact on drug absorption kinetics, followed by capillary density and drug diffusivity.

conclusionOur modelling framework proved feasible in predicting local transport and systemic absorption from the injection site of small molecules. Understanding the effect of these properties and how to model them may help to greatly expedite the development process.