Pharmacokinetics of an orally-available aurora kinase inhibitor

Pharmacometrics Ltd consulted with a USA- and UK-based biotechnology company on pharmacokinetic analysis of the preclinical and phase I clinical trial data obtained with a novel orally-dosed inhibitor of aurora kinases A and B.  Human PK parameters were predicted from the preclinical data by allometric scaling, and later compared with the measured human values.

Development of a pharmacokinetic-pharmacodynamic model of a cyclin-dependent kinase inhibitor

Using a biomarker for apoptosis, Pharmacometrics has developed a PK-PD model of an orally active cdk inhibitor. The model can be used to predict the effects of changes in dose and schedule on killing of tumour cells in patients (see Expert Opinion on Drug Discovery 3: 131-143, 2008).

Mathematical modelling of the mitotic spindle assembly checkpoint

When tumour cells develop defects in the mitotic checkpoint, they lose control of chromosome segregation, resulting in aneuploid cells (cells with an abnormal chromosome complement). This leads to the process of tumour progression, in which initially benign tumours become progressively more invasive and metastatic. A quantitative understanding of this process would aid in assessing which components of the checkpoint could provide targets for drug design. In collaboration with mathematicians at the University of Dundee, Scotland, and biologists at Cyclacel Ltd., we have developed a computer model of the spindle checkpoint. This model has been published in Proceedings of the National Academy of Sciences 105: 20215-20220 (2008).

New software for analysis of drug interactions (synergism and antagonism)

A user-friendly implementation of the method of Greco et al. (1990) facilitates quantitation and statistical analysis of drug combination data.  Professor W R Greco (Roswell Park Cancer Institute and State University of New York at Buffalo) has collaborated on this project.  A range of graphical presentations is supported.  For data from synthetic lethal screens, the DPDMODEL can be used to determine whether the combination is more or less selective than the parent drugs, and in conjunction with PK data, can be used to predict results of in vivo combinations from in vitro data.  An abstract of this work has been submitted for presentation at the 2008 annual meeting of the American Association for Cancer Research, San Diego, California, April 2008.

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