Male and female Royal College of Surgeons (RCS) rats were randomized into two balanced groups with or without cyclosporine A (CsA) in drinking water at 210mg/L, an immunosuppressive therapeutic level recommended by published literature. Growth, clinical pathology parameters, along with organ weight and histopathology evaluations were performed after 28, 56, 91 and 118 days of exposure. Blood CsA concentrations were analyzed by LC-MS/MS at day 1, 2, 4 and 7 and at termination. Blood CsA concentrations reached steady level at day 4 and ranged from 1670 to 6310 ng/mL. This range was much higher than the values (~300μg/L) reported in the literature.
Systemic CsA toxicities included decreased body weight, increased ALP, glucose and BUN. Adverse findings attributable to treatment with CsA were observed in the kidney, pancreas, thymus, and bone marrow. The present data clearly indicates that chronic daily oral cyclosporine A exposure at 210mg/L delivered by drinking water in the Royal College of Surgeons rats lead to circulating cyclosporine A levels and systemic toxicities that are underestimated by the current immunosuppressive protocols used to evaluate cell therapy products for the treatment of retinal dystrophy.
Andrews-Zwilling, Y.S., Moradi, E., Madsen, T., Fu, Y.A., Wicks, J.R., White, D., Hanks, C., Liu, J., Bates, D.,Bouchard, G.F., Stricker-Krongrad, A.