Repeat-dose toxicity studies,

The initial strategy for Phase I is to conduct a single-dose safety study in normal volunteers. The first trial demands close 24-hour supervision in a clinical setting. Ethical considerations may, however, demand that only patients be used, for example, when evaluating an anticancer agent with predictable toxicity. A repeat dose tolerance and pharmacokinetic study in normal or patient volunteers is then conducted for chronically administered drugs. These studies will provide the necessary safety information to support efficacy testing. 

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... 

B.26 Sub-Chronic Oral Toxicity Test Repeated Dose 90-Day Toxicity Study in Rodents (2001)... 

B.26 Sub-chronic oral toxicity test. Repeated dose 90-day toxicity study in rodents B.27 Sub-chronic oral toxicity test Repeated dose 90-day toxicity study in non-rodents B.28 Sub-chronic dermal toxicity test 90-Day repeated dermal dose study using rodent species B.29 Sub-chronic inhalation toxicity test 90-Day repeated inhalation dose study using rodent species B.30 Chronic toxicity test... 

MPL Vaccine adjuvant Cardiovascular/respiratory function safety pharmacology study, repeat-dose toxicity in rat (up to 4wks—subcutaneous), rabbit and dog, reproduction (embryo-fetal studies in rat and rabbit) and 2 in vitro genotoxicity studies No adverse effects 40... 

In the evaluation of toxic characteristics of any environmental chemical, determination of oral toxicity using repeated doses may be performed after obtaining initial acute toxicity data. This provides information on possible adverse effects that may arise from repeated exposures to the test chemical over a limited period of time. Although there are major similarities in the 28-day and 14-day oral toxicity studies on rodents, the main difference lies in the time over which the dose is administered and the extent of the clinical and pathologic investigations that might be necessary for the shorter period of test. 

Cardiovascular profiling in vivo Implant telemetry Single (acute) dose Noninvasive telemetry integrated into toxicity studies Repeat (chronic) dose... 

In chronic toxicity studies oral doses of 40, 125 and 400 pmol/kg (14, 43 and 138 ]ig/kg) have been used in mice and rats, and 2, 16 and 80 pmol/kg (0.7, 5.5 and 28 mg/kg) in dogs [1]. In one additional oncogenicity study in female rats, 5, 10 and 40 pmol g (1.8, 3.5 and 14 mg/kg) were used [2]. On repeated daily administration of 40 pmol/kg and above to rats, a complete inhibition of stimulated acid secretion is found 2 h after dosing, whereas 20 to 60% inhibition depending on the dose still remains 24 h after dosing (Fig. 1). With 10 pmol/kg, about 80% inhibition is found 2 h after dosing at steady state during repeated administration. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

S3B Pharmacokinetics Guidance for Repeated Dose Tissue Distribution Studies Toxicity Testing... 

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

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

In vivo mutagenicity studies Further repeat-dose study in the rat Second developmental toxicity study Two-generation fertility study in the rat Chronic fish toxicity study Biodegradation simulation studies... 

Long-term repeat-dose (a 12 months) study in the rat Further toxicity study to investigate specific concerns Two-generation fertility study in the rat (if not part of the Annex VII data)... 

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). 

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