Category: Clinical Pharmacology
Purpose: Subcutaneously (SC) injected biotherapeutics including monoclonal antibodies (mAbs) have become a major business driver in the pharmaceutical industry, mainly because they enable patients self-injection of drug, increasing patient-compliance and reducing clinical cost.1 A major hurdle in developing SC injectables lies in understanding and predicting drug absorption at the injection site and its impact on the whole-body biodistribution.2 A multiscale QSP model is herein developed with first principles to bridge the physicochemical attributes of a drug product and the biomechanical properties of SC tissue for predicting the in vivo fate of biotherapeutics.
Methods: The human SC tissue is treated as a poroelastic medium, where vascular and lymphatic vessels are implicitly modeled. The diffusion-advection equation and flow laws of porous media are used to simulate the spatiotemporal evolutions of tissue porosity, pressure and drug concentration in the SC injection site based on mass continuity theory and vascular permeation. The local drug release profile is further integrated with whole-body physiologically-based pharmacokinetic (PBPK) model to predict drug exposure in tissue level.3,4
Results: During the injection period, drug droplet displaces the SC tissue and expands the local porosity. A counter pressure is then applied to the drug bolus, leading to the Darcy’s flux after injection. During the post-injection period, the mass transport of drug fluid is driven by the concentration gradient between the drug bolus and surrounding tissue, pressure gradient caused by the changes of tissue porosity, interstitial fluid flow and lymphatic absorption collectively. The locally augmented porosity and pressure of SC tissue drop off rapidly during the initial hour, followed by slow restoration to their static values. Diffusion and advection across the bolus boundary contribute primarily to the local concentration distribution of drug during the first couple hours, while the advection driven by the interstitial fluid flow becomes a dominant force thereafter. Drug absorption through lymphatic permeation occur mainly outside the injection point due to the diffusive and advective transport, with a diminishing rate, until drug dissipates in the SC tissue. Concurrently, the absorbed drug fluxed into the central lymph and then entered the systemic circulation. The local drug release profiles and the time course of plasma drug concentration simulated from our model are validated with radiolabeled studies of model drugs in SC tissue and clinical trial results.5,6 Diffusion coefficient and lymphatic permeability of drug products, as well as the locally accessible lymphatic vessel density and tissue porosity are predicted to play important roles in the biotherapeutics absorption from the SC tissue.
Conclusion: The mass transport of SC injected biologics is initially dominated by diffusion and advection driven by the drug concentration or pressure evolution, whereas the drug transport is determined by the interstitial fluid flow and lymphatic absorption subsequently.
1. Ecker DM, Jones SD, Levine HL 2015. The therapeutic monoclonal antibody market. mAbs 7(1):9-14.