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Research ArticleArticle

Exploratory Translational Modeling Approach in Drug Development to Predict Human Brain Pharmacokinetics and Pharmacologically Relevant Clinical Doses

W. Kielbasa and R. E. Stratford Jr.
Drug Metabolism and Disposition May 2012, 40 (5) 877-883; DOI: https://doi.org/10.1124/dmd.111.043554
W. Kielbasa
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R. E. Stratford Jr.
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Abstract

The central nervous system (CNS) pharmacokinetics (PK) of drugs that have pharmacological targets in the brain are not often understood during drug development, and this gap in knowledge is a limitation in providing a quantitative framework for translating nonclinical pharmacologic data to the clinical patient population. A focus of translational sciences is to improve the efficiency of clinical trial design via a more judicious selection of clinical doses on the basis of nonclinical data. We hypothesize that this can be achieved for CNS-acting drugs based on knowledge of CNS PK and brain target engagement obtained in nonclinical studies. Translating CNS PK models from rat to human can allow for the prediction of human brain PK and the human dose-brain exposure relationship, which can provide insight on the clinical dose(s) having potential brain activity and target engagement. In this study, we explored the potential utility of this translational approach using rat brain microdialysis and PK modeling techniques to predict human brain extracellular fluid PK of atomoxetine and duloxetine. The results show that this translational approach merits consideration as a means to support the clinical development of CNS-mediated drug candidates by enhancing the ability to predict pharmacologically relevant doses in humans in the absence of or in association with other biomarker approaches.

Footnotes

  • This work was sponsored by Eli Lilly and Company.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.043554.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain barrier
    BCB
    blood cerebrospinal fluid barrier
    bECF
    brain extracellular fluid
    ECF
    extracellular fluid
    NE
    norepinephrine
    DHPG
    3,4-dihydroxyphenylglycol
    CSF
    cerebrospinal fluid
    PK
    pharmacokinetic(s)
    hNET Ki
    human norepinephrine transporter inhibition constant
    NET
    norepinephrine transporter
    hSERT Ki
    human serotonin transporter inhibition constant
    CBC
    duloxetine concentration associated with brain cells
    CB
    whole-brain concentration after duloxetine infusion
    CECF
    brain extracellular fluid concentration
    VECF
    brain extracellular fluid volume
    VBC
    brain cell volume
    VB
    total brain volume
    CuP
    unbound duloxetine plasma concentration
    CP
    plasma concentration
    CuBC
    duloxetine unbound brain cell concentration
    CCSF
    duloxetine CSF concentration
    fuP
    unbound plasma fraction
    fuB
    unbound brain fraction
    PET
    positron emission tomography
    QD
    once daily
    RO
    receptor occupancy.

  • Received October 31, 2011.
  • Accepted January 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (5)
Drug Metabolism and Disposition
Vol. 40, Issue 5
1 May 2012
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Research ArticleArticle

PREDICTING HUMAN BRAIN PHARMACOKINETICS

W. Kielbasa and R. E. Stratford
Drug Metabolism and Disposition May 1, 2012, 40 (5) 877-883; DOI: https://doi.org/10.1124/dmd.111.043554

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Research ArticleArticle

PREDICTING HUMAN BRAIN PHARMACOKINETICS

W. Kielbasa and R. E. Stratford
Drug Metabolism and Disposition May 1, 2012, 40 (5) 877-883; DOI: https://doi.org/10.1124/dmd.111.043554
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