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Pharmaceutics 2018, 10(1), 14;

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

Ministry of Health Malaysia, Block E1, E3, E6, E7 & E10, Parcel E, Federal Government Administration Centre, Putrajaya 62590, Malaysia
Applied Health Research Group, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK
Aston Pharmacy School, Aston University, Birmingham B4 7ET, UK
Author to whom correspondence should be addressed.
Received: 2 January 2018 / Revised: 8 January 2018 / Accepted: 12 January 2018 / Published: 17 January 2018
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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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 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 ± 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 ± 17.32 ng/mL and a HC Cmax 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. View Full-Text
Keywords: PBPK; pharmacokinetics; CNS; brain; blood–brain barrier; microdialysis PBPK; pharmacokinetics; CNS; brain; blood–brain barrier; microdialysis

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Zakaria, Z.; Badhan, R. Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics. Pharmaceutics 2018, 10, 14.

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