Evaluation of the Efficiency of Targeting of Antitumor Drugs: Simulation Analysis Based on Pharmacokinetic/Pharmacodynamic Considerations

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Abstract
Antitumor drugs can be classified into two groups; cell cycle phase nonspecific (type I) and specific (type II) drugs. The cytotoxic activity of type I drugs depends on the time-concentration product (AUC), whereas 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 factor for evaluating the efficiency of any delivery system for antitumor drugs. In the present study, we examined the factors governing the cytotoxicity of drugs in tumors based on a hybrid perfusion model. It is suggested that the increase in tumor tissue binding of drug results in an increased unbound drug mean residence time (MRTT,U), leading to 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 (AUCT,U) is unaffected by the extent of drug binding. We also found that the symmetrical increase in the permeability-surface area products (PS) for drug influx (PSinf) and efflux (PSeff) across the tumor plasma membrane results in the unaltered and reduced antitumor activity for the type I and type II drugs, respectively, due to the unaltered AUCT,U and to the reduced MRTT,U. The kinetic analysis suggests that the increase in PSinf/PSeff ratio results in the increased cytotoxic activity of both type I and type II drugs. Collectively, optimization of the antitumor activity can be attained by increasing the tissue binding for type II drugs and by increasing PSinf and/or by decreasing PSeff 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 altering each process (tissue binding and membrane permeability for the influx and efflux processes) which governs the characteristics of drug distribution to tumors.