Download An in vitro-based PBPK model for prediction of BBB permeability

S3.4
An in vitro-based PBPK model for prediction of BBB permeability and unbound brain
concentrations of drugs: evaluation with microdialysis data
Kathryn Ball, François Bouzom, Jean-Michel Scherrmann, Xavier Declèves
Objectives
To build a whole body PBPK model utilizing in vitro input parameters for blood-brain barrier
drug permeability in order to simulate unbound brain concentrations, and to use brain
microdialysis data to evaluate model predictions
Methods
In vitro literature data for morphine and oxycodone, including permeability in Caco-2 cells
and brain endothelial cell cultures, were used to predict BBB permeability in the rat whole
body PBPK model. A scaling factor for BBB transporter activity (relative activity factor,
RAF) was estimated by fitting the model to in vivo literature data from microdialysis and
whole brain homogenate concentrations. The PBPK model was transposed to human, and
simulations and a model sensitivity analysis were performed.
Results
RAFs for morphine and oxycodone were obtained using the rat model, resulting in a good
agreement with microdialysis data. Human simulations were performed using these values,
and the potential impact of inter-species differences discussed. The sensitivity analysis
demonstrated the influence of RAF and brain binding (fu,brain) on the model’s prediction of
unbound brain concentrations.
Conclusion
In vitro-in vivo extrapolation (IVIVE)-based PBPK models are valuable for the a priori
prediction of drug concentration-time profiles, and can be used for the prediction of unbound
brain concentrations in human before clinical studies. Due to the improvements in in vitro
models of the BBB, this type of PBPK model will be increasingly used during drug
development. Microdialysis data is important in confirming the preclinical predictions and
estimating certain model parameters. Further development of the PBPK model will be
considered, both in terms of structural complexity, and relative transporter protein abundance
data in vitro versus in vivo.