Development of a pharmacokinetic/pharmacodynamic (PK/PD)-simulation system for doxorubicin in long circulating liposomes in mice using peritoneal P388

Abstract

The objective of this study was to develop a simulation system that optimizes the pharmacokinetic parameters of drug carriers for anticancer agents in order to maximize their anticancer effects. The pharmacokinetic/pharmacodynamic (PK/PD) model of doxorubicin (DOX) encapsulated into liposomes has been developed for mice and each parameter required for simulations was obtained in the peritoneally inoculated P388 leukemia model in mice. PK parameters, which describe the dispositions of free and liposomally encapsulated DOX, were obtained by kinetic analysis of experimental data in this study, as well as from literature. PD parameters, which describe the growth and death rate of cancer cells in vivo, were also determined. The PK/PD model developed in this study is capable of simulating the time course of the number of cancer cells quantitatively and evaluating the significance of each parameter on the carrier system for DOX. Simulations based on the PK/PD model predict the optimum rate of drug release from long circulating liposomes as 0.06 h(-1) for maximum anticancer effect. Thus, this simulation system provides useful information relative to the optimization of drug carriers for DOX.