Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model.
BACKGROUND
ISATX247 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 ISATX247 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 ISATX247 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 ISATX247 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 ISATX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISATX247 was 120 +/- 32 ng/mL and cyclosporine was 189 +/- 130 ng/mL. The average area under the curve 0-12 for ISATX247 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 ISATX247 and 48 +/- 12% for cyclosporine.


CONCLUSIONS
Allografts in monkeys treated with ISATX247 survived significantly longer than those treated with cyclosporine. On the basis of survival times and degree of calcineurin inhibition, ISATX247 is a more potent immunosuppressive agent than cyclosporine in this nonhuman primate model of renal-allograft transplantation.
Gregory
Clare R
CR
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616-8745, USA.
Kyles
Andrew E
AE
Bernsteen
Lynda
L
Wagner
Gerhardt S
GS
Tarantal
Alice F
AF
Christe
Kari L
KL
Brignolo
Lori
L
Spinner
Abigail
A
Griffey
Stephen M
SM
Paniagua
Ricardo T
RT
Hubble
Richard W
RW
Borie
Dominic C
DC
Morris
Randall E
RE
D000818:Animals; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D016019:Survival Analysis; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology
C484071:voclosporin; D016572:Cyclosporine