Repeated-dose toxicity studies

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test OECD... 

TABLE 2.7. Duration of Repeated Dose Toxicity Studies to Support Clinical Trials and Marketing3... 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

TABLE 7.7. FDA Draft Recommendation for Type I Immunotoxicity Test That Can Be Included in Repeated Dose Toxicity Studies... 

Usually a functional observational battery (FOB) is integrated into a rodent (rat) repeat dose toxicity study to meet this requirement... 

Matsuzawa, T., Hashimoto, M, Nara, H., Yoshida, M., Tamura, S. and Igarashi, T. (1997). Current status of conducting function tests in repeated dose toxicity studies in Japan. J. Toxicol. Sci. 22 374—382. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Duration of Repeated Dose Toxicity Studies to Support Phase 1 and Phase 2 Clinical Trials in the EU, and Phase 1, 2, and 3 Clinical Trials in the United... 

Minimum Duration of Repeated Dose Toxicity Studies... 

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Original Guideline, adopted 22 March 1996)... 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

Repeated dose toxicity studies differ with respect to duration. In principle, any duration is possible, but for the sake of harmonization it has become necessary to limit the study durations to a number of standard durations in the test guideline studies. 

Dose-response relationship and threshold for any of the adverse toxicological effects observed in the repeated dose toxicity studies. 

Table 4.12 summarizes the various OECD test guideline studies for repeated dose toxicity in more detail, including the parameters examined in each test, in order to provide a brief overview of the similarities and differences between the various repeated dose toxicity studies. 

The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) is, for the repeated dose toxicity part, concordant with the standard 28-day oral toxicity study (OECD TG 407) except for use of pregnant females and longer exposure duration (about 6 weeks for males and approximately 54 days for females) in the combined study compared to the standard 28-day study. 

If local effects are clearly identified after repeated dosing, a NOAEL and/or LOAEL should be derived for these effects in addition to NOAEL and/or LOAEL derived for systemic effects. Supportive evidence for the occurrence or absence of local effects after repeated dermal and inhalation exposure may be available from the total toxicity profile of the substance. It should be noted that lack of evidence for local effects in any type of study (i.e., skin or eye irritation, sensitization, repeated dose toxicity study by routes other than the route of interest) does not exclude the possible occurrence of local effects upon repeated respiratory or dermal exposure (EC 2003). 

Substances, which are skin or eye irritating or corrosive after single exposure (Section 4.5) should be suspected of inducing local effects upon repeated respiratory exposure to low concentrations. In contrast, local effects reported from skin sensitization studies as well as dermal repeated dose toxicity studies are not predictive of local effects on the respiratory tract. In addition, observations from irritation and/or sensitization studies as well as repeated dose inhalation toxicity studies are not predictive of local effects on the skin upon repeated dermal exposure (EC 2003). 

The number of repeated dose toxicity studies available for a substance under evaluation is likely to be variable, ranging from none to the 28-day repeated dose toxicity guideline study, to a series of guideline studies for some substances, including subchronic and/or chronic studies. There may also... 

In circumstances where repeated dose toxicity studies have not been carried out according to conventional guidelines and/or GLP, data from such studies could be considered to be equivalent to data generated by corresponding test guideline methods if the following conditions are met ... 

The information that can be obtained from the various types of repeated dose toxicity studies is... 

Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessment of Immunotoxicity... 

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