BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.
BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.
Authors: A Hart; J M Smith; M A Skeans; S K Gustafson; A R Wilk; S Castro; A Robinson; J L Wainright; J J Snyder; B L Kasiske; A K Israni Journal: Am J Transplant Date: 2019-02 Impact factor: 8.086
Authors: Monika Vig; Wayne I DeHaven; Gary S Bird; James M Billingsley; Huiyun Wang; Patricia E Rao; Amy B Hutchings; Marie-Hélène Jouvin; James W Putney; Jean-Pierre Kinet Journal: Nat Immunol Date: 2007-12-02 Impact factor: 25.606
Authors: Jonathan M Bisaillon; Rajender K Motiani; José C Gonzalez-Cobos; Marie Potier; Katharine E Halligan; Wael F Alzawahra; Margarida Barroso; Harold A Singer; David Jourd'heuil; Mohamed Trebak Journal: Am J Physiol Cell Physiol Date: 2010-01-27 Impact factor: 4.249
Authors: Tim A Weaver; Ali H Charafeddine; Avinash Agarwal; Alexandra P Turner; Maria Russell; Frank V Leopardi; Robert L Kampen; Linda Stempora; Mingqing Song; Christian P Larsen; Allan D Kirk Journal: Nat Med Date: 2009-07-05 Impact factor: 53.440