An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

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.

Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy

“…Portions of the cell cycle model have been published in Chassagnole et al[32]. The description of the mitotic spindle assembly checkpoint is based on that described by Mistry et al [38] and by Kamei et al[39]. …”

Pharmacodynamic Modelling of Biomarker Data in Oncology

“…Biomarkers of aurora kinase A inhibition include mitotic arrest, increased phosphorylation of histone H3, and decreased aurora kinase A autophosphorylation. This model was used as the PD component of a PK/PD model [43] which was used to describe biomarker dynamics in tumour-bearing mice treated with the aurora kinase A/B inhibitor CYC116 [41]. …”