A general model for time-dissociated pharmacokinetic-pharmacodynamic relationships exemplified by paclitaxel myelosuppression

Background: Hematologic toxicity after cancer chemotherapy and other drug effects that occur late compared to the exposure are usually modeled with use of some summary exposure variable such as the area under the concentration-time curve (AUG model) or the time of exposure above a threshold concentration (threshold model), An underlying assumption for both of these models is that the drug exerts a direct effect while present in the body and that it is the time integral of this direct effect that is related to the ultimate observed effect, either linearly (AUG model) or by a step function (threshold model), We propose a more general model that allows this relationship to be characterized by a nonlinear continuous function. Methods: Data on survival fraction of neutrophiles and time course of leukopenia from 92 courses of paclitaxel therapy in 21 patients with breast or ovarian cancer was related to paclitaxel concentration-time profiles with the AUG, threshold, and general models, The properties of the general model were also investigated with use of simulations. Results: For both pharmacodynamic end points, the general model described the data significantly better than the AUC or threshold models. Conclusion: The general model is an extension to the present way of relating concentration-time profiles to late-effect measures, and it may provide an improved description of the concentration-response relationship and more accurate predictions of the ultimate effect when doses and schedules are varied, It can explain complex relationships between concentration-time profiles and the observed effect, and predictions from it lack some of the counterintuitive properties that the AUC or threshold model have when extrapolations are made.