An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor

Hiroko Kamei, Robert C. Jackson, Daniella Zheleva, Fordyce A. Davidson

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anticancer drugs. In this paper we present for the first time an integrated pharmacokinetic–pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.
    Original languageEnglish
    Pages (from-to)407-434
    Number of pages28
    JournalJournal of Pharmacokinetics and Pharmacodynamics
    Volume37
    Issue number4
    DOIs
    Publication statusPublished - Aug 2010

    Fingerprint

    Aurora Kinases
    Pharmacokinetics
    M Phase Cell Cycle Checkpoints
    Pharmaceutical Preparations
    Aurora Kinase B
    Aurora Kinase A
    Prometaphase
    Kinetochores
    Anaphase
    Metaphase
    Mitosis
    Microtubules
    Cell Division
    Cell Cycle
    Cell Culture Techniques
    Chromosomes
    4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine

    Keywords

    • PK–PD models
    • Spindle assembly checkpoint
    • Aurora kinase inhibitors

    Cite this

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    abstract = "The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anticancer drugs. In this paper we present for the first time an integrated pharmacokinetic–pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.",
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    An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor. / Kamei, Hiroko; Jackson, Robert C.; Zheleva, Daniella; Davidson, Fordyce A.

    In: Journal of Pharmacokinetics and Pharmacodynamics, Vol. 37, No. 4, 08.2010, p. 407-434.

    Research output: Contribution to journalArticle

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