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J Natl Cancer Inst. 1990 Aug 15;82(16):1321-6.

Pharmacologically guided phase I clinical trials based upon preclinical drug development.

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Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857.


Since our original proposal 4 years ago, considerable support has evolved for the concept of pharmacologically guided dose escalation in phase I clinical trials with new anticancer drugs. The original focus has been broadened to develop additional links between preclinical testing and phase I clinical trials. Recent experiences with very lengthy phase I trials for at least eight drugs have provided particular impetus for this project. The original pharmacodynamic hypothesis for the proposal was equal toxicity at equal plasma levels. Specifically, two facets of the concept were that (a) dose-limiting toxicity correlates with, and in turn is predicted by, drug concentrations in plasma and (b) that the quantitative relationship between toxicity and drug exposure, as measured by plasma drug concentration times time (C x T), holds across species. If true, this hypothesis would suggest that dose escalations in humans could be safely based on measurement of drug levels in plasma, rather than on empirical escalation schemes. In addition to the collection of a larger retrospective data base to validate this hypothesis, practical results have already been achieved. In two studies sponsored by the National Cancer Institute (NCI), the escalation pattern was prospectively modified on the basis of measurements of drug levels in plasma. In addition, for three NCI-sponsored drugs, more careful matching of schedules between clinical and preclinical testing produced entry doses that were up to 25 times higher than doses used in standard procedures. Consequently, the phase I trials for each drug were completed with a savings of 12-24 months. As a result of work in both the United States and Europe, a substantial collection of data now demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.

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