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

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 HC C(max), t(max) 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 C(max) of 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 FC C(max) of 62.12 ± 17.32 ng/mL and a HC C(max) of 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.