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significantly increased or decreased by concomitant food intake, further studies may be required in which the time interval between drug administration and food ingestion may be varied to determine at what time interval the interaction loses significance. |
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Other drug interaction studies include coadministration with medications that may influence absorption or elimination, i.e., antacids, cimetidine, theophylline, probenecid, drugs that influence protein binding, and also drugs that are likely to be extensively coadministered in the patient population, particularly drugs in the same therapeutic class. Most regulatory agencies are sensitive to this topic and the number of these types of studies has increased during recent years. In many instances the number of drug interaction studies is dictated by a check list approach on a what if basis. As will be described later in this chapter, this approach is cost ineffective. While some interaction studies are unpredictable, for example the type and extent of a drug-food interaction [16,17], many others may be predicted or discounted on a mechanistic basis dictated, for example, by the degree of protein binding, the extent of metabolism, the specific metabolism enzymes involved, and also on the presence or absence of active membrane transport. If these types of mechanistic guidelines are not applied, then the number of drug interaction studies conducted during a clinical development program will continue to expand to unrealistic and uneconomic proportions. |
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Relative bioavailability/bioequivalence between the dosage forms used in clinical trials and market-image dosage forms are often treated as check box items. However lack of equivalence between clinical and market-image formulations can have a disastrous impact on a development program possibly requiring the shifting of additional resources to reformulate and to conduct additional clinical bioequivalence trials. This sort of information should be generated as early as possible in a clinical development program. Achieving this may put considerable pressure on Product Development resources to develop the market-image formulation early, but is nonetheless a more attractive alternative than having to reformulate during the final stages of a development program and perhaps having to conduct additional clinical trials if equivalence between clinical and marketed formulations cannot be achieved. |
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V. The Need for Change, Rationalization, Efficacy, and Economy |
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As described in the introduction to this chapter, the disciplines of pharmacokinetics and drug metabolism have evolved to achieve their current high level of involvement in pharmaceutical R & D, and regulatory agencies worldwide demand an ever-increasing amount of pharmacokinetic and metabolism data. |
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