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pharmacokinetics and pharmacodynamics in special patient populations, then plasma or urine sampling for drug analysis during general large-scale clinical safety and efficacy trials should be minimal and should be restricted to a small proportion of study sites. If, on the other hand, a mixed effect modeling approach is used to describe pharmacokinetics and pharmacodynamics in special patient populations, then studies in special populations are deemphasized and plasma and urine sampling in safety and efficacy trials needs to be more rigorous. As noted earlier, the place of mixed effect modeling in the analysis of clinical data continues to evolve. Its current contribution to NDA submissions tends to be nonpivotal but this could change depending on user friendliness of the kinetic and statistical computer software and the philosophical position taken by regulatory agencies. |
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One type of clinical study that has caused much controversy has been that of determining absolute systemic availability of orally administered compounds in humans. This writer has been involved in many debates weighing the benefits of obtaining these data against the risks. The benefits are clearly associated with complete pharmacokinetic characterization, with particular implications regarding interactions affecting absorption, first-pass presystemic clearance, and providing data that may be critical for novel dosage form development. The risks are principally associated with having to do additional intravenous toxicology and toxicokinetic studies and also a clinical absolute availability study, with all the associated costs, notwithstanding the potential for unexpected toxicity resulting from intravenous doses. |
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While the principal emphasis in this chapter has been to do fewer studies, particularly in clinical development, the case for obtaining absolute bioavailability data for an orally administered drug provides an exception. Despite the obvious risks involved, the absence of absolute bioavailability information for a new drug candidate is not only scientifically negligent in failing to describe a vital pharmacokinetic characteristic, but is also certain to give rise to repeated questions and challenges from regulatory agencies. Such questions are always contentious and, almost without exception, cause or contribute to delayed marketing approval of a new chemical entity. Carrying out clinical absolute bioavailability studies is both sensible and responsible from both scientific and safety perspectives and is favored or demanded by most regulatory agencies. |
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Some areas of pharmacokinetic involvement that should receive greater or less emphasis during clinical development are summarized in Table 5. |
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VI. Summary and Conclusions |
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Pharmacokinetics and drug metabolism have evolved to play critical roles in drug discovery and development. The increasing maturity of these disciplines, the relative ease of obtaining pharmacokinetic and metabolism data, and also |
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