1. Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood–Brain Barrier and Assess Target Site Disposition
- Author
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Parsshava Mehta, Amira Soliman, Leyanis Rodriguez-Vera, Stephan Schmidt, Paula Muniz, Monica Rodriguez, Marta Forcadell, Emili Gonzalez-Perez, and Valvanera Vozmediano
- Subjects
PBPK qualification ,BBB permeability ,CNS ,brain modeling ,target site disposition ,translational modeling ,Pharmacy and materia medica ,RS1-441 - Abstract
The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of
- Published
- 2024
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