EVALUATION OF THE EFFICIENCY OF TARGETING OF ANTITUMOR DRUGS - SIMULATION ANALYSIS BASED ON PHARMACOKINETIC PHARMACODYNAMIC CONSIDERATIONS/

Antitumor drugs can be classified into two groups; cell cycle phase no nspecific (type I) and specific (type II) drugs. The cytotoxic activit y of type I drugs depends on the time-concentration product (AUG), whe reas that of type II drugs is time-dependent. Therefore, not only the AUC in the target organ, but also the exposure time is an important fa ctor for evaluating the efficiency of any delivery system for antitumo r drugs. In the present study, we examined the factors governing the c ytotoxicity of drugs in tumors based on a hybrid perfusion model. It i s suggested that the increase in tumor tissue binding of drug results in an increased unbound drug mean residence time (MRT(T,U)), leading t o the increased activity of type II drugs. In contrast, the cytotoxic activity of type I drugs is unaffected by the alteration in the tissue binding, since the intracellular AUC defined for unbound drugs (AUC(T ,U)) is unaffected by the extent of drug binding. We also found that t he symmetrical increase in the permeability-surface area products (PS) for drug influx (PSinf) and efflux (PSeff) across the tumor plasma me mbrane results in the unaltered and reduced antitumor activity for the type I and type II drugs, respectively, due to the unaltered AUC(T,U) and to the reduced MRT(T,U). The kinetic analysis suggests that the i ncrease in PSinf/PSeff ratio results in the increased cytotoxic activi ty of both type I and type II drugs. Collectively, optimization of the antitumor activity can be attained by increasing the tissue binding f or type IT drugs and by increasing PSinf and/or by decreasing PSeff fo r type I and type II drugs. The present simulation. study was carried out by considering the pharmacodynamic features of antitumor drugs and was a method of predicting how the antitumor activity may change on a ltering each process (tissue binding and membrane permeability for the influx and efflux processes) which governs the characteristics of dru g distribution to tumors.