Abstract
In the present review, we will present a method for the prediction of a maximal tolerated dose, MTD, of anititumor drugs in humans based on toxicokinetic, pharmacodynamic and toxicodynamic informations obtained from findings in the literature and our previous studies. This method may be useful in conducting a clinical study of a new antitumor drug efficiently and performing a cancer chemotherapy at a proper dosage schedule. Antitumor drugs can be classified into two types, depending on their cytotoxic mechanisms, type 1 drugs, cell cycle phase-nonspeciffc agents, i.e., area under the curve for drug concentration versus time (AUC)-dependent drugs, and type 2 drugs, cell cycle phase-specific agents, i.e., those that are exposure time-dependent. There was an excellent correlation between mouse AUC at LD10 and human AUC at MTD in comparison with that between mouse LD10 and human MTD for type 1 drugs but not for type 2 drugs. For type 1 drugs, the correlation between mouse AUC at LD10 and human AUC at MTD was better for unbound than for total drug. Pharmacokinetically guided dose escalation strategy proposed by Collins et al.is useful for type 1 drugs; species differences in protein binding should, however, be considered.
