Repeated dose toxicity definition

Data from repeat-dose toxicity studies are essential for CTAs in the early stages of development of a compound, but are superseded once there is a reasonable amount of human data. Any target organs that are identified in the toxicity studies should be monitored in clinical trials. Definitive data on the effects derived from clinical trials will show whether the animal studies are predictive of the effects in humans. This information can then be used to help interpret findings in reproductive toxicity studies, such as whether general toxicity in the adult is relevant. If adult toxicity in animals is deemed relevant, the exposure at which it occurs can be used to estimate the clinical relevance of any reproductive effects. If toxic effects in animals are induced at exposures greatly in excess of the clinical exposure, then they might not be clinically relevant. 

The TDAR assay is believed to be one of the more predictive functional assays for assessing the immunotoxicity potential of drug candidates. This assay could be used to investigate the functional consequences of alterations seen in repeated-dose toxicity studies and/or clinical trials, and to provide an early read on the immunomodulatory potential of discovery candidates. The TDAR assay has been shown to predict immunotoxicity hazard. However, because of the inherent inter-animal variability seen in the TDAR particularly in outbred species, the assay should not be used as the definitive test but as an integral component of a weight-of-evidence approach for evaluating immunotoxicity risk. 

The objectives of the typical subchronic study fall into three categories. The first is to broadly define the toxicity (and, if one is wise, the pharmacology and hyperpharmacology) of repeated doses of a potential therapeutic agent in an animal model (Traina, 1983). This definition is both qualitative (what are the target organs and the nature of the effects seen ) and quantitative (at what dose levels, or, more important, at what plasma and tissue levels, are effects definitely seen and not seen ). 

Prior clinical trials have attempted to discern the best manner in which to administer chemotherapy when combined with radiation. It may be given concurrently with standard radiotherapy, an alternating or split-course radiotherapy schedule, or in a sequential fashion as induction (prior to definitive treatment) or adjuvant (following definitive treatment) chemotherapy. Concomitant chemoradiotherapy is the use of both modalities simultaneously. Alternating chemoradiotherapy is the use of systemic chemotherapy for a definitive duration, followed by radiotherapy for a specified period followed by repeated alternations of the two modalities. Split-course chemoradio-therapy usually involves concomitant systemic doses of chemotherapy combined with radiation therapy for a specified duration followed by a rest period, and then the regimen is repeated. This approach allows planned treatment breaks for toxicity recovery. 

At both these times, thigh muscle contained a higher concentration of 2-PAM I than abdominal muscle, but a lower concentration of III. Dogs and rabbits appear, therefore, to tolerate repeated daily intravenous doses of 2-PAM I at 30 mg/kg or of III at 10 mg/kg during a period of 6-8 wk when the dally doses are suspended during each weekend. Because in this and the other studies reviewed the animals were killed at or soon after the end of the period of administration of an oxime, there has been no opportunity to judge whether repeated administration of an oxime may initiate some alteration in normal structure or function that will result eventually in a definite lesion. No truly chronic study of the toxicity of an oxime has been found. Thus, possible cryptic toxic effects of this type of compound have never been assessed. 

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