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An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor

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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

Harvard

Kamei, H, Jackson, RC, Zheleva, D & Davidson, FA 2010, 'An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor' Journal of Pharmacokinetics and Pharmacodynamics, vol 37, no. 4, pp. 407-434.

APA

Kamei, H., Jackson, R. C., Zheleva, D., & Davidson, F. A. (2010). An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor. Journal of Pharmacokinetics and Pharmacodynamics, 37(4), 407-434doi: 10.1007/s10928-010-9166-0

Vancouver

Kamei H, Jackson RC, Zheleva D, Davidson FA. An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor. Journal of Pharmacokinetics and Pharmacodynamics. 2010 Aug;37(4):407-434.

Author

Kamei, Hiroko; Jackson, Robert C.; Zheleva, Daniella; Davidson, Fordyce A. / An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor.

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

Research output: Contribution to journalArticle

Bibtex - Download

@article{f0897c470755460e998732f4e6022e6e,
title = "An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor",
author = "Hiroko Kamei and Jackson, {Robert C.} and Daniella Zheleva and Davidson, {Fordyce A.}",
year = "2010",
volume = "37",
number = "4",
pages = "407--434",
journal = "Journal of Pharmacokinetics and Pharmacodynamics",
issn = "1567-567X",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor

A1 - Kamei,Hiroko

A1 - Jackson,Robert C.

A1 - Zheleva,Daniella

A1 - Davidson,Fordyce A.

AU - Kamei,Hiroko

AU - Jackson,Robert C.

AU - Zheleva,Daniella

AU - Davidson,Fordyce A.

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - PK–PD models

KW - Spindle assembly checkpoint

KW - Aurora kinase inhibitors

U2 - 10.1007/s10928-010-9166-0

DO - 10.1007/s10928-010-9166-0

M1 - Article

JO - Journal of Pharmacokinetics and Pharmacodynamics

JF - Journal of Pharmacokinetics and Pharmacodynamics

SN - 1567-567X

IS - 4

VL - 37

SP - 407

EP - 434

ER -

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