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

Zaril Zakaria, Raj Badhan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalPharmaceutics
Volume10
Issue number1
DOIs
Publication statusPublished - 17 Jan 2018

Bibliographical note

© 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

Keywords

  • PBPK; pharmacokinetics; CNS; brain; blood–brain barrier; microdialysis

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