Cell cycle checkpoint models for cellular pharmacology of paclitaxel and platinum drugs.

A pharmacokinetic-pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose-response curves as exposure time becomes long.