EXTENSION OF THE 4-WEEK SAFETY STUDY FOR DETECTING IMMUNE-SYSTEM IMPAIRMENT APPEARS NOT NECESSARY - EXAMPLE OF CYCLOSPORINE-A IN RATS

A 4-week study was conducted to shed light on the question of whether compounds impairing immune homeostasis may escape the standard safety testing, Wistar rats were orally treated with cyclosporin A at dosages of 0 (control: olive oil), 1, 5 or 25 mg/kg/day, Ten rats/sex/group ( study segment 1) were not immunized while six other rats/sex/group (st udy segment 2) were immunized 4 days before killing to perform a plaqu e forming cell (PFC) assay; All rats were subjected to routine safety evaluations (OECD guideline 407) and determination of IgM and IgG seru m levels, Other immune parameters were evaluated using cells from sple en and mesenteric lymph nodes (segment 1). Effects on safety parameter s were similar for immunized and non-immunized rats. A slight decrease of body weight gain (males, 25 mg/kg) accompanied slight clinical che mical and histomorphologic evidence of renal tubulotoxicity, Changes i n safety parameters indicative of immune system alterations were: incr eased thymic corticomedullary ratio (greater than or equal to 5 mg/kg) and (25 mg/kg) minimal lymphopenia, low thymus weight, thymic cortica l lymphocytolysis and low lymphoid cellularity of spleen and lymph nod es, They were associated with (males at greater than or equal to 1 mg/ kg) dose-related decreases of T-cell receptor(+) and CD4(+) cells and increases of CD8(+) cells, and decreased PFC (greater than or equal to 5 mg/kg) and lymphoproliferative responses to mitogens and alloantige ns (25 mg/kg), There were no changes in natural killer activity. The c onventional assay identified the drug as a potential immunomodulator. Specific immune assays (phenotyping, PFC) improved the threshold of de tection. These results did not support the incorporation of specific i mmune tests in the standard 4-week study protocol.