Division of Mathematics, University of Dundee, Dundee, UK.
J Pharmacokinet Pharmacodyn. 2010 Aug;37(4):407-34. doi: 10.1007/s10928-010-9166-0. Epub 2010 Aug 8.
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 anti-cancer 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.
纺锤体组装检查点是一种细胞周期监测机制，可确保在有丝分裂过程中染色体在细胞分裂前正确分离。极光激酶在有丝分裂进展中起着至关重要的作用，因此，已开发出极光激酶的小分子抑制剂作为一类新的潜在抗癌药物。在本文中，我们首次提出了 CYC116（一种已知的 Aurora 激酶 A 和 B 的抑制剂）对纺锤体组装检查点的功能作用的综合药代动力学-药效学模型。我们使用该模型模拟了两种常见的实验系统：细胞培养和口服给药的小鼠，并对 CYC116 的一系列剂量和药物给药方案的作用进行了预测。该模型表明，需要达到一个临界的药物浓度峰值才能导致动粒微管附着异常。该模型还预测，只要超过这个阈值浓度，高剂量的口服药物就会在任何受损细胞中引起大量异常附着。然而，带有异常附着的细胞进入后期的比例与血浆浓度维持在阈值以上的总时间有关。此外，我们的模型表明，前期/中期的长度是药物剂量的非线性函数，这个时间段可以延长或缩短。最后，该模型预测 CYC116 的疗效存在很强的饱和效应。我们讨论了这些预测对使用 CYC116 和其他类似 AK 抑制剂的进一步药物试验可能产生的影响。
