Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Biopharmaceutical Modeling
• Drug Distribution Studies

Background:

• Minimal physiologically-based pharmacokinetic (mPBPK) models offer a practical approach for analyzing drug disposition using limited data.
• Traditional mammillary models often lack the physiological relevance needed for complex drug molecules like monoclonal antibodies (mAbs).

Purpose of the Study:

• To develop and validate a second-generation mPBPK model for monoclonal antibodies (mAbs).
• To accurately predict mAb extravascular distribution and disposition using only plasma concentration-time data.
• To provide a more physiologically relevant alternative to mammillary models for mAb pharmacokinetic analysis.

Main Methods:

• Developed a second-generation mPBPK model incorporating convection and interstitial fluid dynamics.
• Categorized tissues into 'leaky' and 'tight' compartments based on vascular endothelial structure.
• Applied the model to analyze pharmacokinetic data from two mAbs in mice and ten mAbs in humans with linear kinetics.

Main Results:

• The mPBPK model effectively captured plasma pharmacokinetic profiles for all studied mAbs.
• Predictions of interstitial fluid concentrations aligned with experimental measurements in mice for specific mAbs.
• The model successfully estimated vascular reflection coefficients, plasma clearance, and transcapillary escape rates for mAbs.
• Identified that elimination from interstitial fluid provided better model fits for a subset of human mAbs.

Conclusions:

• The proposed mPBPK model provides a feasible and robust method for assessing mAb extravascular distribution using plasma data.
• This model generates more physiologically relevant parameters compared to mammillary models, enhancing practical value.
• It serves as a valuable intermediate step towards full physiologically-based pharmacokinetic modeling for monoclonal antibodies.