Repeateddose Toxicity Studies

Repeated-dose studies are designed to identify safe levels of the drug following treatment regimens that are designed to provide continuous exposure of the animals to the test drug. Ideally, the route of administration should mimic that planned in man, and the animal studies should involve longer durations of exposure and higher doses than those planned clinically. The type and duration of specific studies, and which ones are needed relative to different stages of clinical development, were mentioned previously (Federal Register November 25 1997). Protocols must specify the number of animals per group, numbers of groups and experimental procedures to be carried out, and standard versions of these have been available for some time. In general, for initial repeated-dose studies, protocols require the use of three dose groups plus a control, and a minimum of 10 rodents and three non-rodents per sex per group. Doses must be selected that will allow for the identification of toxic effects at the highest dose as well as a no-effect level at the middle or lowest dose.

Usual experimental procedures include the determination of body weights and food consumption on at least a weekly basis, evaluation of hematology and blood chemistry parameters during the treatment period, ophthalmoscopic examinations, the recording of macroscopic examinations at necropsy, and the determination of organ weights. A complete histopathological examination of tissues from animals is required. In rodent studies, this can take the form of examination of all high-dose and control animals and the examination of target organs at the two lower doses. In non-rodent studies, it is typical to examine tissues from all animals in the study.

It is crucial that plasma concentrations of drug are measured in these studies to allow for determination of effects on the basis of exposure. Frequently this is a more appropriate measure of comparing effects in animals and man, since rates of absorption, distribution, and excretion can vary extensively between these species. This aspect, now commonly referred to as 'toxicokinetics', has been outlined in an ICH guideline (Federal Register March 1 1995). This guideline specifies minimum requirements in terms of number of time points examined, number of animals per time point, and the requirements for calculation of various pharmacokinetic parameters such as Cmax, AUC, etc. These will become important for com parison with human data as it becomes available later.

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