E. Fuse et al., APPLICATION OF PHARMACOKINETICALLY GUIDED DOSE-ESCALATION WITH RESPECT TO CELL-CYCLE PHASE SPECIFICITY, Journal of the National Cancer Institute, 86(13), 1994, pp. 989-996
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.