Integrating In-vitro Permeability Assays within PBPK Modeling to Predict CNS Distribution of Standard and Engineered...

Area of Science:

• Pharmacokinetics and Drug Delivery
• Neuroscience and Neurology
• Biotechnology

Background:

• Antibody delivery to the brain is limited by blood-brain barrier (BBB) permeability.
• Physiologically-based pharmacokinetic (PBPK) models currently lack a priori predictive power for brain disposition.
• In-vitro permeability assays (Papp) offer antibody-specific transport data but are not integrated into PBPK models.

Purpose of the Study:

• To develop and validate an integrated in-vitro-in-vivo-extrapolation (IVIVE) PBPK framework.
• To utilize Papp values for a priori prediction of antibody concentrations in cerebrospinal fluid (CSF).
• To enhance the predictive capability of PBPK models for brain drug delivery.

Main Methods:

• Developed an IVIVE PBPK framework using PK-Sim®/MoBi® software.
• Integrated in-vitro Papp values to estimate antibody-specific brain transport parameters.
• Compared predictions with observed CSF exposures in rats against a conventional modeling approach.

Main Results:

• The IVIVE-PBPK framework significantly reduced the average prediction error for CSF exposure from 296.1% to 53.4%.
• The model accurately predicted brain disposition for both standard and engineered antibodies.
• The approach did not require pre-existing in-vivo cerebrospinal fluid data.

Conclusions:

• Papp-informed PBPK modeling enables accurate, a priori mechanistic prediction of antibody brain exposure.
• This framework supports antibody candidate selection in brain drug development.
• The approach reduces the necessity for extensive animal studies in preclinical brain drug development.