Preclinical toxicity

Such sentinel workflow uses a prediction to select compounds for a more expensive screen that can confirm predicted hazards (liabilities, such as toxicity). It is, provably, the best workflow in contexts where a low prevalence of the hazard is anticipated, and where there is a backstop means further downstream (e.g., preclinical toxicity testing) for detecting hazards before humans are exposed. This workflow then allows the compounds predicted as safe to bypass the expensive hazards screen, without unacceptable risk, and can add significant value in terms of external screening costs or avoiding use of what may be a bottleneck resource. 

Host-resistance assays can be used to assess the overall immunocompetence of the humoral or cell-mediated immune systems of the test animal (host) to fend off infection with pathogenic microbes, or to resist tumorigenesis and metastasis. These assays are performed entirely in vivo and are dependent on all of the various components of the immune system to be functioning properly. Thus, these assays may be considered to be more biologically relevant than in vitro tests that only assess the function of cells from one source and of one type. Since these assays require that the animal be inoculated with a pathogen or exogenous tumor cell, they cannot be performed as part of a general preclinical toxicity assessment, and are thus classified as Type 2 tests in the revised Redbook. These assays are also included as Tier II tests by the NTP. 

Indirect Immunotoxic Effects. A problem related to data interpretation is how to distinguish secondary effects that may indirectly result in immunotoxicity from the primary effects of immunotoxicity in preclinical toxicity studies. Various factors may produce pathology similar to that of an immunotoxin ... 

Gad, S.C. (1996b). Preclinical toxicity testing in the development of new therapeutic agents. Scand. J. Lab. Anim. Sci. 

The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5-1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen the minimum lethal dose—the smallest dose that is observed to kill any experimental animal and, if necessary, the median lethal dose (LD50)—the dose that kills... 

Drug discovery requires a host of inputs, new ideas, design and synthesis of substances, evaluation of preclinical toxicity tests in animals, clinical studies in human volunteers, permission to market the drug, postmarketing studies of safety, and comparison with other medicines. Drug development is highly technical and enormously expensive, with a success rate of 1 in 10,000 compounds. 

For a drug that has never been used in humans previously, the initial step that a pharmaceutical company must take is to perform preclinical toxicity studies involving appropriate in vitro systems or whole animals. The FDA usually requires that dose-related toxicity be determined in at least two mammalian species (routinely rodents). The toxicity information obtained from these studies can then be used to make risk/benefit assessments and help determine the acceptability of the drug for testing in humans, and to estimate a safe starting dose. 

Animal tissues are collected at necropsy of humanely euthanized, purpose-bred laboratory animals immediately following death. Some nonhuman primates used for tissue acquisition may be wild caught. The animals used are preferably matched as closely as possible to that of the strain or origin of the animals to be used for preclinical toxicity testing. 

CURRENT PRACTICES IN THE PRECLINICAL TOXICITY ASSESSMENT OF PEPTIDES... 

Investigators are currently assessing the potential safety and efficacy of a mixed modality treatment regimen (i.e., combining a DNA vaccine with a viral vector). In this example preclinical toxicity and biodistribution studies were conducted in mice using a DNA vaccine in combination with a modified vaccinia virus Ankara based HIV vaccine to support a phase 1 trial in healthy HIV-1-uninfected volunteers [77,78],... 

The absorption, distribution, metabolism, and excretion in the species used in the toxicology studies should be discussed. Quantitative or notable qualitative differences in ADME between the various animal species and humans should be discussed, as well as any references to observed species differences in toxicity and extrapolation of the findings to humans. The significance of these findings to the interpretation of the results of the carcinogenicity, bioassay, and other preclinical toxicity studies should be considered. 

Although the kidney has been identified as a major target organ for all bisphosphonates at the high doses used in preclinical toxicity studies, a clear therapeutic window still exists, enabhng bisphosphonates to be safely administered in general clinical use for the inhibition of bone resorption. However, there are differences in the therapeutic indices between individual agents and in their pharmacokinetic and pharmacodynamic profiles in patients with both normal and impaired renal function. 

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