Abstract
Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.
Highlights
Quantification of central nervous system (CNS) drug levels in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) is often achieved by complex in vivo experimental procedures, such as microdialysis
With development of therapeutic drugs targeted to the Central nervous system (CNS) lagging behind development of drugs for other therapeutic areas there is an urgent requirement to better predict CNS drug disposition
The application of brain microdialysis and PET imaging techniques will provide a true quantitative understanding of the temporal brain concentrations, but the techniques and equipment needed for their applications in understanding CNS drug disposition is often a limiting factor to their widespread use
Summary
Quantification of central nervous system (CNS) drug levels in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) is often achieved by complex in vivo experimental procedures, such as microdialysis. Ball et al [43] described the development of a whole-body physiologically based pharmacokinetic (PBPK) model for the prediction of unbound drug concentration-time profiles in the rat brain, utilising a mechanistic approach to described drug transfer across the blood–brain barrier. Which is very similar to the in vitro protein abundance in L-mdr1a cells, 15.2 fmol/μg protein [54,55], but higher in comparison to that measured in human brain capillaries (6.06 fmol/μg protein) [54] Such findings suggest data derived from L-mdr1a cells could be incorporated into predictive physiologically-based pharmacokinetic models and may prove useful in assessing CNS drug disposition for P-glycoprotein substrates. In the present study we describe a predictive, physiologically-based pharmacokinetic model of the rat CNS which incorporates discrete brain and CSF components and is able to predict brain-to-plasma and CSF-to-plasma ratios using in vitro permeability parameters and drug protein/tissue binding data. We developed a mouse whole-body PBPK model which, when populated with mouse physiological parameters and L-mdr1a cell-derived data, allowed prediction of mouse Kpuu,brain and CSF:Plasmau (see Supplementary Information)
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