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Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood-Brain Barrier and Assess
Parsshava Mehta1, Amira Soliman1,2, Leyanis Rodriguez-Vera3
1Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA.
Pharmaceutics
|February 24, 2024
Summary
Physiologically based pharmacokinetic (PBPK) models can predict drug concentrations in the central nervous system (CNS). This tool aids in developing new CNS drugs by assessing their ability to cross the blood-brain barrier (BBB).
Area of Science:
- Pharmacokinetics and Drug Development
- Neuroscience and Central Nervous System (CNS) Research
- Computational Biology and Modeling
Background:
- High failure rates in CNS drug development are linked to poor understanding of drug exposure at the target site.
- Effective tools are needed to evaluate blood-brain barrier (BBB) permeability for CNS drug candidates.
- Physiologically based pharmacokinetic (PBPK) models integrate drug and system characteristics to predict target site distribution.
Purpose of the Study:
- To qualify a PBPK platform model for predicting CNS drug concentrations.
- To assess the model's utility when human data is scarce and transporter activity is minimal.
- To establish a reliable tool for CNS drug development and dosage evaluation.
Main Methods:
- Collected literature data on acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam in rats and humans.
- Extrapolated human BBB permeability from rat data using inter-species BBB surface area differences.
- Utilized a PBPK platform model to simulate and predict drug concentrations in the CNS.
Main Results:
- The PBPK model achieved high accuracy in predicting CNS drug concentrations, with 85% (rat) and 100% (human) of predictions within a 1.25-fold criterion for AUC and Cmax.
- The overall geometric mean fold error (GMFE) was less than 1.25 across all tested drugs and species.
- Demonstrated successful prediction of human CNS concentrations for drugs passively crossing the BBB.
Conclusions:
- The PBPK platform is a validated tool for predicting human CNS drug concentrations for passively distributed drugs.
- This model can aid in selecting promising CNS drug candidates early in development.
- The PBPK platform can inform the evaluation of new dosing regimens for existing CNS medications.
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