Immunotoxicity assessment, approaches

AN INTEGRATED APPROACH TO PRECLINICAL AND CLINICAL IMMUNOTOXICITY ASSESSMENTS... 

INTEGRATED APPROACH TO PRECLINICAL CLINICAL IMMUNOTOXICITY ASSESSMENTS 325... 

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 basis of the recommended approach to a hazard assessment of the potential immunotoxicity of a substance is that many immunotoxic substances can be identified via the standard tests for systemic toxicity. Special smdies to characterize effects of concern for immunotoxicity are used only when necessary for adequate hazard assessment. The nature of special smdies, and when they should be conducted, need to be decided on a case-by-case basis. A tiered approach to the identification of immunotoxic hazard in routine toxicology is described in WHO/IPCS (1996). 

The scope of the toxicity studies when surrogate molecules have been used includes pharmacology studies, subchronic and chronic studies, reproductive toxicity studies, immunotoxicity studies, and even carcinogenicity studies. Short-term assays like safety pharmacology studies are too short for there to be an antisense effect, so we have not used the surrogate approach in these assays. However, when safety pharmacology endpoints are included in subchronic or chronic studies, surrogates are assessed. 

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. 

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