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.

Publication DOI: https://doi.org/10.3390/pharmaceutics10010014
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Applied Health Research Group
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Funding: Ministry of Health Malaysia
Uncontrolled Keywords: PBPK; pharmacokinetics; CNS; brain; blood–brain barrier; microdialysis
PURE Output Type: Article
Published Date: 2018-01-17
Accepted Date: 2018-01-12
Authors: Zakaria, Zaril
Badhan, Raj (ORCID Profile 0000-0002-0904-9324)

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