Toxicity testing, repeat-dose

GL31 Safety Repeat-dose toxicity test Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose toxidly testing... 

Test Guidelines Adopted for Repeated Dose Toxicity Testing... 

Currently, there are no validated and regulatory accepted in vitro methods for assessing repeated dose toxicity. Numerous in vitro systems have been developed over the last decades and have been discussed and summarized in recent ECVAM reports on repeated dose toxicity testing (Worth and Balls 2002, Prieto et al. 2005, Prieto et al. 2006). Human in vitro data, particularly on kinetics and metabolism, and in vitro test data from well-characterized target organ and target system models on, e.g., mode of action(s)/mechanism(s) of toxicity may be useful in the interpretation of observed repeated dose toxicity. 

The adopted test guideline methods for repeated dose toxicity testing include a number of parameters relevant for the evaluation of a substance s immunotoxic potential. Furthermore, a specific test guideline for immunotoxicity has also been adopted by the US-EPA. These test methods are addressed in Section 4.7.3.1 and Tables 4.11 and 4.12. 

Box 3.2 shows the toxicity package t)q)ically generated before a Phase I trial. These trials are usually conducted in males, and thus do not require formal reproductive toxicity studies. In the United States, women can be included in early trials without any animal reproductive toxicity if special precautions are taken to ensure that pregnancy does not occur. A histopathological assessment of the effects of the test compound on the male reproductive tract is made in the repeat-dose toxicity tests. 

Where functional cross-reactivity to at least one of the usual toxicology species is present, and appropriate assays for PK and PD have been developed, the clinical candidate can be used in a relatively conventional developmental toxicity program with that species (preferably the rat, for which the most background data will be available). Following early sub-chronic repeat-dose toxicity testing in the rodent (usually up to 1 month s duration), with accompanying PK/PD data, the reproductive study program can be planned as appropriate to the circumstances. 

Other tests can reveal effects indicative of potential reproductive toxicity. Examples include the dominant lethal test, fertility assessment by continuous breeding, repeated-dose toxicity testing, and cancer studies where the gonads are subjected to pathological examination. These tests, however, provide information only on effects after dosing adult animals and are therefore not addressed below. 

Toxicological information on repeat dose toxicity testing, sub-chronic toxicity study (90 day) and reproductive toxicity testing a two-generation study will be needed... 

Repeated dose toxicity tests are usually performed in two species, one rodent and one non-rodent, using equal numbers of both sexes in each group and 10 rodents or 4-6 non-rodents per group. Rats and dogs are a commonly used combination. Veterinary products which are not used in food producing animals may be tested in only one species, e.g. the target species. 

For environmental chemicals, no dedicated OECD test guidelines exist but extensions to 28 day repeat dose toxicity testing (TG... 

V. Because pharmaceuticals are normally tested for toxicity in rodent repeated dose toxicity tests and because there is no longer a requirement for an acute high dose rodent toxicity test, the assessment of genotoxicity (e.g., bone marrow micronucleus test or other tissue/endpoint) should be integrated, if feasible, into the rodent repeated dose toxicity study to optimize animal usage. 

Sakuratani Y, Sato S, Nishikawa S, Yamada J, Maekawa A, Hayashi M (2008) Category analysis of the substituted anilines studied in a 28-day repeat-dose toxicity test conducted on rats correlation between toxicity and chemical structure. SAR QSAR Environ Res 19, 681-96. 

Prior to filing an IND, a number of additional studies and tasks must be completed. A formal characterization of the structure and properties of the compound must be completed, methods to analyze the strength, purhy stability of the pure compound and any formulation must be completed and bioanalytical methods to analyze drug in pharmacology and toxicology studies must be developed. Regulatory toxicity in two species, at minimum a single dose toxicity test and a repeat dose toxicity test that matches or exceeds the duration of the planned clinical trial, must be completed. Once a clinical plan is developed, the... 

---