Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model

Background. ISA TX 247 is a novel calcineurin inhibitor that has shown more potency than cyclosporine in vitro. This is the first study to compare the survival times of renal allografts in nonhuman primates treated with either ISA TX 247 or cyclosporine. Methods. Adult, male cynomolgus monkeys were divided into blood-group compatible and mixed-lymphocyte, stimulation-mismatched, donor-recipient pairs. Heterotopic renal transplantation and bilateral native nephrectomies were performed. The monkeys were placed into either an ISA TX 247 or cyclosporine treatment group. Both groups were dosed twice daily to maintain a 12-hour drug-trough level of 150 ng/mL. Whole-blood concentrations of ISA TX 247 and cyclosporine, complete blood counts, and serum chemistry profiles were performed three times a week. Euthanasia was performed if the serum creatinine concentration became 7 or more mg/dL or a serious complication developed. Results. The group receiving ISA TX 247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISA TX 247 was 120±32 ng/mL and cyclosporine was 189±130 ng/mL. The average area under the curve 0-12 for ISA TX 247 was 6045±1679 ng/mL/hr and for cyclosporine was 4919±823 ng/mL/hr. The average calcineurin inhibition at trough blood concentrations was 80±11% for ISA TX 247 and 48±12% for cyclosporine. Conclusions. Allografts in monkeys treated with ISA TX 247 survived significantly longer than those treated with cyclosporine. On the basis of survival times and degree of calcineurin inhibition, ISA TX 247 is a more potent immunosuppressive agent than cyclosporine in this nonhuman primate model of renal-allograft transplantation.