SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

Area of Science:

• Biopharmaceutics and Pharmacokinetics
• Mathematical Modeling
• Subcutaneous Drug Delivery

Background:

• Accurate prediction of drug absorption after subcutaneous injection requires understanding initial device-formulation-tissue interactions.
• Existing models often lack detailed mechanistic insights into the injection process and its impact on drug disposition.

Purpose of the Study:

• To develop a mechanistic, physiologically based biopharmaceutics model (SubQ-Sim) for subcutaneous injection.
• To predict device-formulation-tissue interactions during injection, including backpressure and formulation behavior.
• To establish a foundation for predicting drug binding, degradation, distribution, and absorption.

Main Methods:

• Developed SubQ-Sim, a mathematical model integrating subcutaneous tissue substructures and drug disposition dynamics.
• Incorporated literature-derived parameters for healthy and diseased subjects.
• Accounted for physiological 'life events' (temperature, exercise, stress) impacting pharmacokinetics.

Main Results:

• The model accurately predicts injection backpressure based on injection rate, volume, and fluid viscosities.
• It describes depot shape, formulation/protein concentrations, and predicts backflow/losses from premature needle withdrawal.
• Explored the impact of type 2 diabetes and hyaluronidase on injection pressure.

Conclusions:

• SubQ-Sim successfully predicts critical initial conditions for subcutaneous drug absorption: tissue pressure, depot characteristics, and formulation losses.
• This model provides essential starting parameters for subsequent drug absorption predictions.
• The next publication will detail the absorption model and clinical validation.