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

Clare R. Gregory, Andrew E. Kyles, Lynda Bernsteen, Gerhardt S. Wagner, Alice F Tarantal, Kari L. Christe, Lori Brignolo, Abigail Spinner, Stephen M Griffey, Ricardo T. Paniagua, Richard W. Hubble, Dominic C. Borie, Randall E. Morris

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 ISA TX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISA TX247 was 120±32 ng/mL and cyclosporine was 189±130 ng/mL. The average area under the curve0-12 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.

Original languageEnglish (US)
Pages (from-to)681-685
Number of pages5
JournalTransplantation
Volume78
Issue number5
DOIs
StatePublished - Sep 15 2004

Fingerprint

Primates
Cyclosporine
Allografts
Kidney
Calcineurin
Kidney Transplantation
Haplorhini
voclosporin
Heterotopic Transplantation
Euthanasia
Macaca fascicularis
Blood Cell Count
Immunosuppressive Agents
Lymphocyte Activation
Blood Group Antigens
Nephrectomy
Serum
Creatinine
Pharmaceutical Preparations

Keywords

  • Cyclosporine
  • ISA247
  • Kidney transplantation
  • Nonhuman primate

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model. / Gregory, Clare R.; Kyles, Andrew E.; Bernsteen, Lynda; Wagner, Gerhardt S.; Tarantal, Alice F; Christe, Kari L.; Brignolo, Lori; Spinner, Abigail; Griffey, Stephen M; Paniagua, Ricardo T.; Hubble, Richard W.; Borie, Dominic C.; Morris, Randall E.

In: Transplantation, Vol. 78, No. 5, 15.09.2004, p. 681-685.

Research output: Contribution to journalArticle

Gregory, CR, Kyles, AE, Bernsteen, L, Wagner, GS, Tarantal, AF, Christe, KL, Brignolo, L, Spinner, A, Griffey, SM, Paniagua, RT, Hubble, RW, Borie, DC & Morris, RE 2004, 'Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model', Transplantation, vol. 78, no. 5, pp. 681-685. https://doi.org/10.1097/01.TP.0000131950.75697.71
Gregory, Clare R. ; Kyles, Andrew E. ; Bernsteen, Lynda ; Wagner, Gerhardt S. ; Tarantal, Alice F ; Christe, Kari L. ; Brignolo, Lori ; Spinner, Abigail ; Griffey, Stephen M ; Paniagua, Ricardo T. ; Hubble, Richard W. ; Borie, Dominic C. ; Morris, Randall E. / Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model. In: Transplantation. 2004 ; Vol. 78, No. 5. pp. 681-685.
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abstract = "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 ISA TX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISA TX247 was 120±32 ng/mL and cyclosporine was 189±130 ng/mL. The average area under the curve0-12 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.",
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T1 - Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model

AU - Gregory, Clare R.

AU - Kyles, Andrew E.

AU - Bernsteen, Lynda

AU - Wagner, Gerhardt S.

AU - Tarantal, Alice F

AU - Christe, Kari L.

AU - Brignolo, Lori

AU - Spinner, Abigail

AU - Griffey, Stephen M

AU - Paniagua, Ricardo T.

AU - Hubble, Richard W.

AU - Borie, Dominic C.

AU - Morris, Randall E.

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N2 - 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 ISA TX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISA TX247 was 120±32 ng/mL and cyclosporine was 189±130 ng/mL. The average area under the curve0-12 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.

AB - 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 ISA TX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISA TX247 was 120±32 ng/mL and cyclosporine was 189±130 ng/mL. The average area under the curve0-12 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.

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KW - ISA247

KW - Kidney transplantation

KW - Nonhuman primate

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