Abstract
Purpose.
The objectives of this work were 1) to develop a theoretical pharmacodynamic model that captures dynamic changes resulting from drug/therapy mediated P-glycoprotein (P-gp) induction and 2) to compare the pharmacodynamic outcomes of several doxorubicin (DOX) dosing schemes through simulations.
Methods.
We developed a theoretical model that included a pharmacokinetic (PK) model for intracellular DOX-mediated P-gp induction and a pharmacodynamic (PD) model using a threshold trigger function for tumor cell-kill. In this model, both the level of P-gp induction and rate of tumor cell death were modulated by intracellular DOX concentration. Most model parameters were obtained from literature sources, and a few were either fixed or reasonably estimated.
Results.
Comparative dosing simulations showed that a 10-week constant infusion in which a tumor cell population was continuously exposed to the drug did not produce the best PD profile. On the other hand, dosing schemes where the cell population was initially challenged with a high dose, followed by intermittent dosing, generated the best PD profile. The favorable outcome of the latter dosing schemes was correlated with the lowest expression of P-gp in terms of area under the curve (AUC) during treatment period.
Conclusions.
The simulations led us to conclude that drug resistance, particularly resistance caused by P-gp overexpression, induced during chemotherapy may, in part, be circumvented by designing optimal dosing strategies that minimize P-gp induction.
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Luu, K., Uchizono, J. P-Glycoprotein Induction and Tumor Cell-Kill Dynamics in Response to Differential Doxorubicin Dosing Strategies: A Theoretical Pharmacodynamic Model. Pharm Res 22, 710–715 (2005). https://doi.org/10.1007/s11095-005-2585-8
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DOI: https://doi.org/10.1007/s11095-005-2585-8