Repeated dose toxicity immunotoxicity

TABLE 7.7. FDA Draft Recommendation for Type I Immunotoxicity Test That Can Be Included in Repeated Dose Toxicity Studies... 

The standard repeated dose toxicity guidehne studies include a number of parameters relevant for the evaluation of a substance s immunotoxic potential. While some information on potential immunotoxic effects may be obtained from the evaluation of hematology, lymphoid organ weights, and histopathology in these studies, there are data which demonstrate that these endpoints alone are not sufficient to predict immunotoxicity. In addition to these standard studies, the US-EPA has developed a specific test guideline for immunotoxicity testing in rodents (OPPTS 870.7800). This... 

Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessment of Immunotoxicity... 

The thymus, spleen, and lymphoid tissues aU have immunological function and changes to them can be indicative of adverse effects on the immune system. Indications of immunotoxicity from standard repeated dose toxicity smdies include one or more of the following signs ... 

Immunotoxicity testing guidelines exist for small molecules where the toxicology is largely unpredictable and rodent species are typically used [4]. Despite the lack of a specific guidance on immunotoxicity evaluation until now, most biopharmaceuticals have assessed the immunotoxic potential of the biophar-maceutical as a part of general single- and/or repeat-dose toxicity studies [5,23]. 

Figure 3.3.1-2 Application of the TDAR assay in immunotoxicity assessment. When evaluating unintended immunosuppression, the TDAR assay may be conducted when evidence of immunotoxicity is seen in repeated-dose toxicity studies. In these instances, the assay should be conducted prior to Phase 3 or earlier, depending on factors such as the severity of the findings and the intended patient population. The TDAR assay also could be used early in the drug development process to screen for immunotoxicity potential. This approach may be useful particularly to help de-risk unintended off-target immunomodulation or when a novel target/mechanisms may alter immune function.

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. 

Toxicity single dose—chimpanzee mouse/ repeat dose— chimpanzee, mouse2 Immunotoxicity chimpanzee, mouse2 Fertility mouse2... 

Institoris L, Siroki O, Desi I, Lesznyak J, Serenyi P, Szekeres E et al (1998) Extension of the protocol of OECD guideline 407 (28-day repeated dose oral toxicity test in the rat) to detect potential immunotoxicity of chemicals. Hum Exp Toxicol 17 206-211... 

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