Pharmacokinetic Studies

In the early stages of drug development, it is important to identify important parameters that relate to the absorption and excretion pathways for the drug. In the later stages of development, studies on the extent of tissue distribution and the identification of metabolites become important. Another reason why this is important is that it assists the investigator in knowing that the appropriate species has been selected for the non-clinical toxicology program. It is important to human safety evaluation that the non-clinical models chosen are representative of the metabolism of the drug in man. Therefore, it is necessary to have pharmacokinetic information early in the program, so that it can be compared to the data generated in the early clinical studies.

Drug metabolism is a highly specialized field, and is increasing in sophistication all the time. A relatively new technique that is available to the preclinical investigator is the use of in vitro methods to establish and confirm similar mechanisms in drug metabolism between animals and man (see Chapter 10). These procedures involve the use of liver slices and/or liver hepatocyte homogenates and can be done in human and animal cultures at the earliest stages of drug development.

Toxicokinetic data is generally obtained from repeated-dose toxicity studies, and generally determines whether: (a) the plasma concentrations of the drug increase in a linear fashion over the range of the increasing doses used in the studies; and (b) plasma concentrations increase over time, suggesting an accumulation of the drug in plasma or tissues; (c) there is a relationship between the plasma concentrations of the drug (or metabolites) and the toxicity associated with higher levels of the drug; and (d) the effects are more closely related to peak concentrations or to overall exposure (measured by the area under the concentration time curve, AUC).

Toxicokinetic data are generally collected on the first day of dosing in a repeated-dose study, and near the last day of dosing, i.e. during the last week, of a 90 day toxicity study. In rodent studies, satellite groups of animals are required due to the blood volumes needed for assay. For larger non-rodents the main study animals can usually provide the samples. Guidelines have been made available covering most aspects of the collection and analysis of these data (Federal Register March 1 1995)

Lastly, pharmacokinetic assessment requires tissue distribution studies in non-clinical models to determine the extent of localization of the drug in tissues. In some situations, where single-dose tissue distribution studies suggest drug localization, a tissue distribution study following repeated dosing may be indicated. The conditions under which such studies may be necessary have been delineated in an ICH guideline (Federal Register March 1 1997)

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