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mentary projects. Prospective planning helps to ensure optimum support to individual programs consistent with R & D priorities and to avoid wasteful knee-jerk activities. Prospective planning applies to all stages in R & D, from discovery through final compilation of regulatory documents, and represents one way, albeit a critical one, to streamline the process. |
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Discovery teams are turning more and more to drug metabolism and pharmacokinetics input to assist in the design of new molecules. Such input may be extremely useful and could considerably shorten the discovery process. On the other hand, commitment of extensive pharmacokinetic and metabolism resources during discovery is potentially wasteful as only a very small percentage of new chemical entities is likely to reach clinical trials. Metabolism support at this stage must be based on utilization of computerized data banks to predict metabolism properties of molecules together with aggressive use of in vitro metabolism systems using animal and human source material to predict in vivo metabolic patterns. This type of work is currently labor intensive, but may not necessarily continue to be so. As metabolism technology advances to become more automated and miniaturized it should be entirely feasible to obtain metabolite characterization of new molecules within hours, with very limited resources. |
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While metabolism input into discovery is essential and is certain to increase, pharmacokinetics input, particularly bioavailability studies, are less useful, extremely labor intensive, and could be phased out or at least decreased without significant loss. In particular, the use of in vivo systemic availability as an initial screen to select a candidate for development represents a costly misuse of resources. It is far more economical, and frequently faster, to use a pharmacologic screen based on activity rather than a pharmacokinetic screen that involves the use of additional animals, multiple blood samplings, and development of analytical procedures for individual compounds. Pharmacokinetic analysis at the discovery stage is wasteful because it is only one of many factors that could affect the prospects of an early drug candidate. |
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In summary, during drug discovery there must be greater emphasis on rapid metabolism screens, possibly but not always requiring radiolabeled compounds, and far less emphasis on pharmacokinetics, which in many instances is both wasteful and inappropriate. |
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C. Nonclinical Development |
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As shown in Table 1, and as discussed earlier, a large number of nonclinical pharmacokinetics studies are conducted both before and after submission of an IND application. Some of these are essential; many are not. Emphasis in nonclinical research has changed from pharmacokinetics to toxicokinetics. Whether |
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