I studies published between 1985 and 1999. Ib studies were excluded. The review included 33 trials with antimetabolites and 60 with other cytotoxic agents. The median number of dose levels tested was nine for antimetabolites and six for other cytotoxic agents. I clinical trials of antimetabolites than would be expected as compared to other classes of cytotoxic agents.
Toxicity thus appears to be incompletely predicted by dose alone for antimetabolites.
Current phase I design may not be ideal for development of these compounds, and should focus on pharmacodynamic endpoints in addition to traditional pharmacokinetic and clinical endpoints. We were interested in exploring this observation further. Since we hypothesized that this ratio would be lowest for antimetabolites, we compared the behavior of this class of drugs to that of all others. Only publications referring to cytotoxic compounds that were tested in solid tumors and in adult populations were included. I trials with starting doses determined by earlier work, with a limited number of dose levels or including combinations of drugs were also excluded, as were compounds abandoned whilst in phase I testing because of unusual or unmanageable toxicity.