A new cyclosporin derivative, SDZ-IMM-125, prolongs renal allograft survival in dogs

Previous studies in vitro and in rodent transplantation models have suggested that an analogue of cyclosporin, SDZ-IMM-125, has immunosuppressive properties at least equivalent to that of cyclosporin. As the bioavailability of the drug was considered to be greater than that of cyclosporin, it was hoped that lower doses could be used with the avoidance of nephrotoxicity. Renal allografts were undertaken between beagle dogs from two partially inbred breeding colonies. After transplantation, SDZ-IMM-125 was given orally at a dosage of 5, 7.5, 10 or 20 mg/kg/day, and graft survival compared to that in dogs given cyclosporin 10 mg/kg or in untreated animals. The results showed that SDZ-IMM-125 is immunosuppressive in dogs and prolongs graft survival up to 50 days at a dosage of 20 mg/kg/day. However, at this dose histological changes suggestive of liver toxicity were observed in one dog, and mild anaemia was produced,but there was no evidence of nephrotoxicity. Absorption profiles suggested that the drug is rapidly absorbed and metabolized, and that a more frequent daily dosage may be appropriate. Overall, there appeared to be no significant advantage for the analogue SDZ-IMM-125 over cyclosporin. The transplant model was associated with a high spontaneous renovascular thrombosis rate, particularly after cyclosporin administration, which was prevented by the daily administration of aspirin.