Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Small molecular pharmaceuticals (SMPs) have been developed for years and used widely in therapy for various diseases. Although it’s recognized that the immunogenicity of SMPs is weak, excessive immunity activated by SMPs is usually occurred in non-clinical and clinical tests, leading to severe consequences such as toxic epidermal necrolysis, drug-induced hypersensitivity syndrome and anaphylaxis. Therefore, it’s critical to assess immunogenicity of systemic-exposed small molecular pharmaceuticals with evaluation system having high throughput and extrapolation. Human Cell Line Activation Test (h-CLAT) is an in vitro method for the assessment of skin sensitization potential of chemicals. We considered that whether h-CLAT can also be used in assessment of systemic response potential of chemicals. Thus, the purpose of this study is to clarify whether there is a relationship between in vitro h-CLAT results and in vivo systemic immune activation induced by SMPs. Compound A induced drug rush when treated to monkeys. Compound B resulted in severe inflammation when treated to rats. It was found they were positive for h-CLAT within 2-fold safety margin. Next, we used anti-bacterial and anti-viral drugs that is reported to induce immune risk in clinical application. Our results showed that short-administration drugs including clindamycin, rifampicin, colistin and spectinomycin are positive for h-CLAT with safety margin less than 10-15-fold, long-administration drugs including raltegravir, ritonavir, nelfinavir and efavirenz are positive for h-CLAT with safety margin less than 4-17-fold. Conclusively, our study indicated h-CLAT results have a good extrapolation into non-clinical/ clinical consequences. And we recommended h-CLAT for screening immunity induction of systemic-exposed small molecular pharmaceuticals in early stage.
