In vitro model for predicting bioavailability of subcutaneously injected monoclonal antibodies

Area of Science:

• Biopharmaceutics
• Drug Delivery
• Pharmacokinetics

Background:

• Monoclonal antibodies (mAbs) are increasingly administered via subcutaneous (SC) injection.
• Preclinical models for SC injection PK/PD prediction have limitations.
• Accurate prediction of clinical outcomes for SC injected mAbs is crucial for dose selection.

Purpose of the Study:

• To introduce and validate a novel in vitro instrument, Scissor, for modeling SC injection sites.
• To establish a predictive model correlating in vitro mAb diffusion with clinical PK/PD outcomes.
• To identify key molecular and formulation properties influencing SC mAb performance.

Main Methods:

• Utilized the Scissor instrument to model mAb diffusion from an SC injection site.
• Emulated systemic circulation using a large volume physiological buffer.
• Applied Hill equation and partial least squares analysis to correlate in vitro data with clinical PK/PD outcomes for eight mAbs.

Main Results:

• Scissor system generated distinct mAb diffusion profiles over 6 hours.
• Protein charge (pI) and formulation properties (viscosity, mAb concentration) significantly influenced mAb movement.
• Demonstrated a strong predictive correlation between in vitro parameters and clinical PK outcomes for the tested mAbs.

Conclusions:

• The Scissor instrument provides a feasible in vitro strategy for assessing SC injected medicines.
• Identified critical drug and formulation properties that dictate SC mAb performance.
• Offers potential for improved formulation selection and first-in-human dosing strategies for SC mAbs.