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Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery

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ABSTRACT

Purpose

The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

Methods

Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (Kp,uu,brain) and cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.

Results

Assessment of Kp,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. Kp,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.

Conclusions

With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.

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Abbreviations

Abrain :

Amount of drug in brain tissue

AUC0−t :

Area under the drug concentration-time curve from zero to t, where t is the last time point with a measurable concentration for an individual dose

AUCtot,brain :

Area under the total drug brain concentration-time curve

AUCtot,plasma :

Area under the total drug plasma concentration-time curve

BBB:

Blood-brain barrier

BCRP:

Breast cancer resistance-associated protein

BCSFB:

Blood-CSF barrier

CB:

Cellular barrier

Cbuffer :

Concentration of compound in the buffer (brain slice method)

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

Ctot,brain :

Total drug concentration in brain

Ctot,plasma :

Total drug concentration in plasma

Cu,brainISF :

Unbound-drug concentration in brain interstitial fluid

Cu,plasma :

Unbound-drug concentration in plasma

ECF:

Extracellular fluid (same as ISF)

ED:

Equilibrium dialysis

fu,brain :

Unbound fraction of drug in brain homogenate

fu,brain,corrected :

Unbound fraction of drug in brain homogenate after applying the correction using the pH partitioning model

fu,hD :

Unbound fraction of drug in diluted brain homogenate

fu,plasma :

Unbound fraction of drug in plasma

ICF:

Intracellular fluid in the brain

ISF:

Interstitial fluid in the brain (same as ECF)

Kp,brain :

Ratio of total brain to total plasma drug concentrations (general annotation)

Kp,brainSD :

Ratio of total brain to total plasma drug concentrations measured after single dose administration

Kp,brainSS :

Ratio of total brain to total plasma drug concentrations at steady-state

Kp,CSF :

Ratio of total plasma to total CSF drug concentrations

Kp,uu,brain :

Ratio of brain ISF to plasma unbound-drug concentrations

Kp,uu,cell :

Ratio of brain ICF to ISF unbound-drug concentrations

Kp,uu,cell,obs :

Kp,uu,cell determined using the combination of brain slice and brain homogenate methods

Kp,uu,cell,pred :

Kp,uu,cell predicted using the three-compartment pH partitioning model

Kp,uu,CSF :

Ratio of plasma to CSF unbound-drug concentrations

Kp,uu,cyto,pred :

Ratio of cytosolic to extracellular unbound-drug concentrations predicted from the pH partitioning model

Kp,uu,lyso,pred :

Ratio of lysosomic to cytosolic unbound-drug concentrations predicted from the pH partitioning model

LC-MS/MS:

Liquid chromatography tandem mass spectrometry

NCE:

New chemical entity

neuroPK:

Neuropharmacokinetics

P-gp:

P-glycoprotein

Vu,brain :

Volume of distribution of unbound-drug in brain (mL·g brain-1)

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ACKNOWLEDGMENTS AND DISCLOSURES

We express our sincere thanks to Koen Wuyts and the Early Drug Developability in vivo Group, Janssen Pharmaceutica for performing the neuropharmacokinetic studies and providing the Kp,brain values. We also gratefully acknowledge the excellent assistance of Britt Jansson (Uppsala University) and Lieve Dillen, Dirk Roelant, Suzy Geerinckx (BA/DMPK, Janssen Pharmaceutica) with the bioanalysis. During the project, Irena Loryan was funded by Janssen Pharmaceutica.

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Authors and Affiliations

  1. Translational PKPD Group, Department of Pharmaceutical Biosciences Associate Member of SciLife Lab,, Uppsala University, Box 591, 751 24, Uppsala, Sweden

    Irena Loryan & Margareta Hammarlund-Udenaes

  2. Clinical Pharmacology, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Vikash Sinha & Achiel Van Peer

  3. Pharmaceutical Development and Manufacturing Science, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Claire Mackie

  4. Neuroscience Discovery, Janssen Research and Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Wilhelmus Drinkenburg

  5. Model Based Drug Development, Janssen Research & Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    An Vermeulen

  6. Early Drug Developability Group CREATe (Community for Research Excellence and Advanced Technologies), Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Denise Morrison

  7. BA/DMPK, Janssen Research and Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Mario Monshouwer

  8. Clinical Pharmacology, Janssen Research & Development, LLC, Titusville, Florida, USA

    Donald Heald

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  1. Irena Loryan
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  2. Vikash Sinha
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  3. Claire Mackie
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  10. Margareta Hammarlund-Udenaes
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Corresponding author

Correspondence to Margareta Hammarlund-Udenaes.

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Figure S1

A. The relationship between the ratios of total brain to total plasma drug concentrations determined at distributional equilibrium (Kp,brainSD) and at steady-state (Kp,brainSS). B. Residual plot. The solid line represents the line of identity. (JPEG 1410 kb)

Figure S2

The relationship between the ratio of brain interstitial fluid to plasma unbound-compound concentrations (Kp,uu,brain) and the ratio of cerebrospinal fluid to plasma unbound-compound concentrations (Kp,uu,CSF). R2 is a coefficient of determination of linear regression analysis. The solid line represents the line of identity. (JPEG 1351 kb)

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Loryan, I., Sinha, V., Mackie, C. et al. Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery. Pharm Res 31, 2203–2219 (2014). https://doi.org/10.1007/s11095-014-1319-1

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  • DOI: https://doi.org/10.1007/s11095-014-1319-1

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