Investigational new drugs
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Investigational new drugs · Aug 2003
Phase I studies of weekly administration of cytotoxic agents: implications of a mathematical model.
Certain toxic effects of cytotoxic anticancer agents typically evolve over weeks. When such agents are administered weekly, these effects are cumulative. With such schedules, good medical practice mandates dose modifications with mild or moderate toxicity in order to avoid progression to serious or life-threatening toxicity. ⋯ We find the concept of maximum tolerated dose inadequate for the determination of best doses. We also suggest a strategy for a new phase I study design which can be used to estimate the "best dose" corresponding to a specified delivery rate. In summary, identification of best doses requires attention, not only to dose limiting toxic events, but also to delivered dose rates and schedule adherence.