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

Zaril Zakaria,Raj Badhan

doi:10.3390/pharmaceutics10010014

Zaril Zakaria, Raj Badhan

Open Access

https://doi.org/10.3390/pharmaceutics10010014

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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 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.

Highlights

Diseases of the central nervous system (CNS) present a considerable socioeconomic burden to healthcare systems, and are expected to exponentially increase with an ageing population
To develop a broader regional CNS physiologically based pharmacokinetic (PBPK) model, this step focused upon the development of a base PBPK model consisting of a whole-body PBPK incorporating a simplistic 1-compartment model of the brain
Validation of the WB-PBPK examined the ability of the model to predict Kpuu,brain in rats for 10 compounds demonstrating passive absorption across the blood–brain barrier (BBB) that were previously used in PBPK modeling by our group [28]

Summary

Introduction

Diseases of the central nervous system (CNS) present a considerable socioeconomic burden to healthcare systems, and are expected to exponentially increase with an ageing population. The majority of CNS disorders that warrant effective drug therapy currently lack examples of successful pharmacotherapy [2]. This failure is often related to the difficulty of finding medicines that can cross the blood–brain barrier (BBB) and enter the brain parenchyma [2]. The BBB presents an almost impermeable barrier to drug delivery for most small molecular weight compounds, often contributing to the attrition of many CNS drug development programs [2,4]. Traditional approaches to tackle this have often focused on determining the steady-state brain distribution of drugs in preclinical species, referred to as the brain-to-plasma ratio or Kpbrain, and correlating this to the molecular properties in order to model/extrapolate brain distribution [5,6]. To account for the driving force for brain delivery (i.e., membrane permeability) and target site receptor occupancies, this is often corrected for the unbound brain-to-unbound plasma ratio (Kpuu,brain) [7,8]

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