APPLICATION OF PHARMACOKINETICALLY GUIDED DOSE-ESCALATION WITH RESPECT TO CELL-CYCLE PHASE SPECIFICITY

Background: In 1986, the concept of pharmacokinetically guided dose es calation (PGDE) was proposed to predict the maximum tolerated dose (MT D) of an antitumor drug in humans from animal data. We have previously shown that antitumor drugs can be classified into two types, dependin g on their cytotoxic mechanisms: type 1 drugs, which are cell cycle ph ase-nonspecific agents, i.e., area under the curve for drug concentrat ion in the plasma versus time (AUC)-dependent drugs; and type 2 drugs, which are cell cycle phase-specific agents, i.e., those that are time dependent, Purpose: The validity of the assumption that the AUC at th e dose lethal for 10% of mice administered drug (LD(10)) is equal to t he AUC at MTD for humans, the premise on which PGDE is based, was exam ined for type 1 and 2 drugs. Methods: Findings in the literature, incl uding those of Collins and co-workers, were retrospectively analyzed. The human/mouse ratios for the AUC were compared with each other and w ith the human/mouse dose ratios, based on milligram per meter square o f body surface area, the measurement currently used in clinical trials of antitumor drugs. For six of the type 1 drugs, the human/mouse rati o for the AUC of total drug (AUC) and that of unbound drug (AUCu), whi ch has been considered a determinant of pharmacologic and toxicologic effects, were also compared. Results: There was an excellent correlati on between log AUC at LD(10) for mice and log AUC at MTD for humans fo r type 1 drugs (r =.898), but not for type 2 drugs (r =.677). For type 1 drugs, the correlation between mouse AUC at LD(10) and human AUC at MTD was better for unbound drug (r =.961) than for total drug (r = .8 92). Conclusions: PGDE is useful for type 1 drugs; differences in prot ein binding between species should, however, be considered when using this method.