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ravaging the pharmaceutical industry, one needs to step back and examine the larger picture of how change can influence a particular discipline and how that discipline in turn must change to productively contribute, and with greater efficiency, to reengineering the R & D process. The title of this section The Dynamics of Change is really a misnomer. Change, particularly that affecting industrial management, is rarely a gradual process but is rather quantum in nature and tends to occur in einen Augenblick! However the actual realization that certain changes have taken place is often gradual such that response to change, although often being considered as prospective, is almost always retrospective in nature; we invariably play catch up. If one cannot truly anticipate change, then in order to survive in the new now existing environment, an organization has to adjust and take compensating actions as rapidly as possible. Otherwise it will not survive in competition with others who may have either anticipated or rapidly adjusted to the new environment. |
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Such is the case with pharmaceutical R & D and, in particular, with the philosophical approach controlling the nature and extent of pharmacokinetics and metabolism contributions to the R & D process. The present situation, in which considerable pharmacokinetics and metabolism resources are wasted in endless assay development and validation, unnecessary kinetic modeling, wasteful and unnecessary preclinical and clinical pharmacokinetics studies, and sometimes mindless support of innumerable clinical studies, many of which are nonpivotal, duplicative, or unnecessary, is wasteful, ineffective, and economically suicidal. While the disciplines of pharmacokinetics and drug metabolism have expanded to a point where they can make meaningful contributions to a wide spectrum drug discovery and development of activities, the question has to be asked as to what extent the contributions provide necessary and useful information to the study of a particular compound and whether they are essential to support safety and efficacy claims in a drug-marketing submission. |
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IV. The Current Situation |
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The process of discovery and development of new chemical entities is summarized in Fig. 1 [9]. |
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As a result of the combined effects of improved analytical methods, greater sophistication of pharmacokinetics and metabolism technology, and increased awareness of the usefulness of kinetic and metabolism data in the discovery process, these disciplines have become intimately involved in the design of new chemical entities. Drug metabolism now plays a critical role in the earliest stages of discovery, particularly in vitro metabolic screening using both animal and human enzyme sources. New chemical entities are also rarely elevated to lead status unless complete pharmacokinetic profiles, in particular absolute bioavailability, elimination half-life, clearance, and distribution volume, are |
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