%0 Journal Article
%T Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics
%A Raj Badhan
%A Zaril Zakaria
%J Archive of "Pharmaceutics".
%D 2018
%R 10.3390/pharmaceutics10010014
%X Central nervous system drug discovery and development is hindered by the impermeable nature of the blood¨Cbrain barrier. Pharmacokinetic modeling can provide a novel approach to estimate CNS drug exposure; however, existing models do not predict temporal drug concentrations in distinct brain regions. A rat CNS physiologically based pharmacokinetic (PBPK) model was developed, incorporating brain compartments for the frontal cortex (FC), hippocampus (HC), ¡°rest-of-brain¡± (ROB), and cerebrospinal fluid (CSF). Model predictions of FC and HC Cmax, tmax and AUC were within 2-fold of that reported for carbamazepine and phenytoin. The inclusion of a 30% coefficient of variation on regional brain tissue volumes, to assess the uncertainty of regional brain compartments volumes on predicted concentrations, resulted in a minimal level of sensitivity of model predictions. This model was subsequently extended to predict human brain morphine concentrations, and predicted a ROB Cmax of 21.7 ¡À 6.41 ng/mL when compared to ¡°better¡± (10.1 ng/mL) or ¡°worse¡± (29.8 ng/mL) brain tissue regions with a FC Cmax of 62.12 ¡À 17.32 ng/mL and a HC Cmax of 182.2 ¡À 51.2 ng/mL. These results indicate that this simplified regional brain PBPK model is useful for forward prediction approaches in humans for estimating regional brain drug concentrations
%K PBPK
%K pharmacokinetics
%K CNS
%K brain
%K blood¨Cbrain barrier
%K microdialysis
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874827/