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| Table 2 Phase 2 Clinical Studies Involving Pharmacokinetics | | Single-dose pharmacokinetics | | Repeated-dose pharmacokinetics | | Absolute systemic bioavailability | | Food effects | | Dose proportionality | | Mass balance | | Metabolism | | Therapeutic monitoring during efficacy and safety studies |
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Phase 2 and into Phase 3 full-scale development. Simultaneously with Phase 2 and 3 clinical studies, additional nonclinical studies are conducted, including special studies such as placental transfer and excretion in milk and bile. However of far greater import is the continuation of metabolism characterization in toxicity species and also long-term general, carcinogenicity, and reproduction toxicology studies, together with associated drug monitoring. During this period there is considerable overlap and interdependence between nonclinical and clinical studies, particularly in the comparison of metabolism pathways in toxicity species and in humans, with consequent validation, or invalidation, of toxicity species relative to human safety. |
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A major activity during Phase 2, and continuing throughout the entire clinical development program, is that of therapeutic drug monitoring during efficacy trials. Consistent with the philosophy of mixed effect modeling [15], appropriate plasma and/or urine sampling during these studies can yield significant information regarding pharmacokinetics and concentration-effect relationships, both regarding efficacy and also tolerance to the drug, across a broad spectrum of patients. |
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The type of expertise generally required to carry out mixed effect modeling analyses has been available for many years, but their application has been plagued by the complexity of the statistics involved, difficulty of obtaining good data that are frequently generated in a noncontrolled clinical environment, difficulty in validating such data and also the pharmacokinetic and statistical computer software involved, problems in interpreting results of such data analysis, and, perhaps more critically, the ambivalent attitude of investigators and regulators regarding the value added by such analysis in a clinical program. Two opposing arguments have frequently been made. The first is that if pharmacokinetic and/or pharmacodynamic data are needed in a specific patient population then appropriate well-controlled studies should be conducted in that population. The counter argument is that such well-controlled studies are largely unnecessary and that sufficient pharmacokinetic and/or pharmacody- |
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