Immunotoxicology assessment in the pharmaceutical industry.

Through several inter-laboratory evaluation studies, selected methods were optimized and evaluated using reference compounds in rodents, to determine their predictive value for detecting toxicity to the immune system. These provide the basis for the OECD, EPA and pending FDA Guidelines. To describe the status of immunotoxicity evaluation using these methods in the pharmaceutical industry, a survey was conducted, and is reported, of ongoing activities among the major pharmaceutical companies. The results describe which assays are performed, how compounds are selected for evaluation; and when, during the drug development process, an evaluation is performed. Finally, the strategy at Sanofi, for the evaluation and application of immunotoxicity methods during the preclinical development of new molecular entities (NMEs) is described. During the past 8 years, Sanofi has evaluated more than 27 NMEs from multiple therapeutic classes as well as four reference compounds (azathioprine, dexamethasone, cyclophosphamide and cyclosporin A). Our experience with multiple animal species (rat, dog and monkey) and immunotoxicity assays selected from the recommended tiers as well as the outcome from the evaluation of our NMEs and reference standards, is described. This experience has led us to believe that immunotoxicology parameters represent an important adjunct for the safety assessment of NMEs. In addition, these methods were easily integrated into the drug development process and yielded an unexpectedly low frequency of positive results. In summary, immunotoxicity can be evaluated on a case-by-case basis driven by pathology or clinical hematology findings, by the drug's indication, the chemical class or indication of the NME evaluated (for example, anti-viral agents), or systematically performed.