Toxicity testing, repeat-dose duration

The duration of repeat-dose studies should be at least as long as the proposed clinical study. These studies are designed to establish a dose-response relationship, define target organ(s) of toxicity, and determine whether observed toxicities are reversible. Evaluation parameters should include not only those routinely performed in the acute studies, but those performed in the additional studies as well. Special tests, such as ophthalmoscopic, electrocardiograph, body temperature, and blood... 

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. 

The 28-day smdies are termed repeated dose (28 days) while the 90-day smdies are termed subchronic. The chronic toxicity test (B.30), requests at least 12 months duration. The preferred species is the rat. 

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. 

Repeat-dose toxicity - rodent and non-rodent species are required. The duration of the test depends on the duration of clinical exposure but many companies conduct two 14-day studies before going into man. Studies should be done using the proposed clinical route... 

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. 

The September 2000 draft guidance considers excipient databases associated with drug products with three different therapeutic durations. For a drug product intended for a 14-day therapy or less, and for infrequent use, the excipient should be tested in acute toxicity studies and in one-month, repeat-dose toxicity studies in two mammalian species (one being a nonrodent), using the intended route of therapeutic administration. 

Intermediate-Duration Exposure. No reliable information is available on the effects of repeated-dose exposure in humans. Limited information is available on the effects of repeated inhalation and oral exposures to 1,1-dichloroethane in animals. The studies reviewed indicate that 1,1-dichloroethane is possibly nephrotoxic, but this effect has only been demonstrated at high doses in one of several species tested. No other toxic effects have been attributed to 1,1-dichloroethane following repeated-dose exposures in animals. An intermediate MRL could not be derived for any routes of exposure. More information on the systemic effects of repeated-dose exposures in animals, particularly by the inhalation route since this is the most likely route of human exposure, would be useful to determine whether nephrotoxic effects observed in one study are an actual result of exposure to 1,1-dichloroethane, to determine if 1,1-dichloroethane reacts like other chlorinated aliphatics (e.g., causes neuro-and liver toxicity), and to more fully assess potential human health hazards from repeated exposure to 1,1-dichloroethane. This latter justification is particularly important since repeated exposure to low levels of 1,1-dichloroethane may be of more concern than short-term exposure to very high levels based on the current use and/or disposal of this chemical. 

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... 

Test compounds can cause both local and systemic adverse effects local effects occur at the sites of initial contact (e.g., injection sites), while systemic effects are observed in organs remote from the site of initial exposure. The degree of toxicity is dependent on the number of exposures or the duration. Effects can be classified as acute (i.e., short term following a single dose) repeated or multiple exposure effects can be referred to as short term (not more than 5% of life span), subchronic (5-20% of life span), and chronic (the entire or a major part of life span). 

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