Toxicity studies rodents/nonrodents

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). 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under the curve are established in rodents and nonrodents. There are two types of toxicity studies single dose and repeated dose. Single... 

Repeated dose chronic toxicity studies are performed on two species of animals a rodent and nonrodent. The aim is to evaluate the longer-term effects of the drug in animals. Plasma drug concentrations are measured and pharmacokinetics analyses are performed. Vital functions are studied for cardiovascular, respiratory, and nervous systems. Animals are retained at the end of the study to check toxicity recovery. Table 5.2 shows the duration of the animal studies, which depends on the duration of the intended human clinical trial. Appendix 6 summarizes the information to be submitted to regulatory authorities. 

Traditionally toxicologists have used at least one rodent and nonrodent species for multidose toxicity studies. The use of two species is important for assessing potential variability of metabolism, for products with extensive distribution, and in cases where a relevant species has not been defined. The rat and dog are selected in most cases, usually on an empirical basis [2] without an open-minded consideration of whether alternate species might be better in terms of biochemistry and metabolism [1],... 

Four-week toxicology studies in rodent and nonrodent The four-week studies are designed for subchronic exposure of rodents and nonrodents to the test article. These studies also look at reversibility of any toxicity observed. Many times these are the pivotal studies used to support the first in human dosing. Toxicokinetic assessments are generally included in repeat-dose toxicity studies. When testing biopharmaceuticals, studies also include assessment and characterization of immune response (immunogenicity). 

On average, 10 to 15 rodents and 3 to 5 nonrodents per sex per group are used for repeat-dose toxicity studies. If possible, 5 rodents and 2 to 3 nonrodents per sex per group should be used for recovery arms. The reuse of nonrodent species is a common practice, particularly for pharmacokinetic studies and in studies in which telemetry is used. Early pilot non-GLP studies for dose selection purposes may also involve the reuse of animals. However, it may not be appropriate in all instances to reuse animals based on the level of... 

These segments can be tested separately or in a combined manner. All stages of development from conception to maturity and the detection of acute and delayed effects of exposure through one complete life cycle should be examined. The standard species are rodents, rats as the preferred rodent species for all study types and, the rabbit as the second nonrodent species for the embryo-toxicity studies. In some rare cases mice or monkeys are used too, if special conditions - usually kinetic data - justify such species. 

Test animal selection—At least two species should be used. One of them should be rodents and the other nonrodents other than rabbits. However, the single dose toxicity study can be eliminated in the studies of nonrodents, when single dose or repeated dose toxicity studies performed as the preliminary studies for the repeated dose toxicity studies are available. 

Standard genotoxicity battery. One-month toxicity (rodent and nonrodent by intended route). Single-study rodent assay to evaluate all phases of reproductive toxicity and a teratology study in a nonrodent... 

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