Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics

Abstract

Central nervous system drug discovery and development is hindered by the impermeable nature of the blood-brain 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 HCCmax,tmaxand 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 ROBCmaxof 21.7 ± 6.41 ng/mL when compared to "better" (10.1 ng/mL) or "worse" (29.8 ng/mL) brain tissue regions with a FCCmaxof 62.12 ± 17.32 ng/mL and a HCCmaxof 182.2 ± 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.