Optimization of anti-tumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling

It has been reported that long circulating liposomes enhanced the antitumor effect of doxorubicin (DOX) by increasing delivery of DOX to tumor tissues . However, there is no quantitative information on the relationship between the antitumor effect and liposomal characteristics governing the release r ate of entrapped drugs, although the importance of drug release-rate contro l from liposomes has been pointed out. Here, we developed a physiological m odel for free and liposomal DOX to calculate the time course of free DOX in the extracellular space and linked this with a cell kill kinetic model to quantify the antitumor effect of DOX. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicoch emical parameters of liposomes, as well as pharmacological or physiological parameters of tumor tissues. The importance of long circulation time of li posomes was confirmed. The optimum rate of drug release from long circulati ng liposomes was found at the release rate constant of around 0.06 h(-1). T his optimum value was not dependent on the tumor proliferation time, sensit ivity of tumor cells to DOX, or the tumor blood flow-rate. This simulation indicated that the optimization of the delivery to tumor tissue by long cir culating liposomes could be possible by changing the release rate of DOX fo r the maximum antitumor effect. (C) 1999 Elsevier Science B.V. All rights r eserved.