Accelerating Subcutaneous Drug Development: A Mechanistic Absorption Model for the Open Systems Pharmacology Framework.

This study describes the implementation of a mechanistic subcutaneous (SC) injection model for the Open Systems Pharmacology platform. As the SC route of administration is gaining increased popularity, there is a growing need for tools to predict, analyze, and understand the SC absorption process and the mechanisms involved. The interplay between molecular, formulation, administration, and physiological properties influences both the rate and extent of drug appearance in circulation. The primary objective of this study was to provide a structural modeling basis for mechanistic simulations of drug absorption after SC administration, considering fundamental molecular properties and systemic disposition characteristics. A key aspect of the model design was the intention to support generalizability and translational application across drug characteristics and species, providing a consistent structure for both small molecules and biologics. The SC model was implemented leveraging the structure and parameterization of PK-Sim to allow unified integration to the whole-body physiologically based pharmacokinetic model. An input-response analysis and a set of case examples were conducted to visualize model responsiveness and illustrate potential application in drug development. The generic framework may also serve as the backbone for further implementations to describe complex injection and formulation dependencies. Collectively, this framework establishes a mechanistic foundation for the simulation of SC drug absorption of both small molecules and biologics, providing a basis for further development and informed evaluation across preclinical and clinical stages within the Open Systems Pharmacology platform.