P-glycoprotein induction and tumor cell-kill dynamics in response to differential doxorubicin dosing strategies: a theoretical pharmacodynamic model.
OBJECTIVE
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.
Luu
Kenneth T
KT
Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211, USA.
Uchizono
James A
JA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D019540:Area Under Curve; D001702:Biopharmaceutics / Q000379:methods / Q000639:trends; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin