Oral efficacy of the macrolide immunosuppressant SDZ RAD and of cyclosporine microemulsion in cynomolgus monkey kidney allotransplantation

Citation
Hj. Schuurman et al., Oral efficacy of the macrolide immunosuppressant SDZ RAD and of cyclosporine microemulsion in cynomolgus monkey kidney allotransplantation, TRANSPLANT, 69(5), 2000, pp. 737-742
Citations number
13
Categorie Soggetti
Medical Research Diagnosis & Treatment
Journal title
TRANSPLANTATION
ISSN journal
00411337 → ACNP
Volume
69
Issue
5
Year of publication
2000
Pages
737 - 742
Database
ISI
SICI code
0041-1337(20000315)69:5<737:OEOTMI>2.0.ZU;2-Y
Abstract
Background 40-O-(2-Hydroxyethyl)-rapamycin (SDZ RAD) is a novel, potent, ma crolide immunosuppressant, Its efficacy in rodent transplantation models pr ovided the rationale for us to evaluate the compound in a more relevant, la rge animal transplantation model. Methods. Life-supporting kidney allotransplantation was performed in cynomo lgus monkeys: rejection was inferred from a rise! in serum creatinine or ur ea and was subsequently confirmed by histopathology, This model was validat ed with the microemulsion formulation of cyclosporine (i.e., Neoral). Two s tudies with a microemulsion formulation of SDZ RAD were performed. First, i n a dose-finding study, the SDZ RAD dose was reduced in a stepwise fashion until rejection occurred, either with SDZ RAD as monotherapy, or in combina tion with :a fixed, suboptimal dose of cyclosporine. Second, an efficacy st udy was performed in which two fixed SDZ RAD doses (0.75 and 1.50 mg/kg/ da y) were evaluated in monotherapy and compared with the same doses of rapamy cin (sirolimus), All immunosuppressants were administered once daily by gas tric gavage, Results, Untreated control animals rejected their grafts between 4 and 8 da ys after transplantation. Cyclosporine (initially at 150 mg/kg/day, reduced to 100 mg/kg/day 2 weeks after transplantation) yielded longterm (>100 day s) rejection-free allograft survival in four of five animals. A 10 mg/kg/da y dose of cyclosporine led to rejection between 10 and 27 days after transp lantation and was considered suboptimal. In the dose-finding study with SDZ RAD monotherapy, rejection occurred in most of the cases (four of six anim als) when a dose level of 0.63 mg/kg/day had been reached. Combined with su boptimal cyclosporine, this threshold SDZ RAD dose was about a-fold lower. In the efficacy study, median grait survival with histologically proven rej ection was 32 days (range 8-91 days, n=6) for 0.75 mg/kg/day SDZ RAD and 59 days (range 28-85 days, n=6) for 1.50 mg/kg/day SDZ RAD. For sirolimus, me dian graft survival was 43 days (range 5-103 days, n=7) for the 0.75 mg/kg/ day dose and 56 days (range 8-103 days, n=8) for the 1.50 mg/kg/day dose. T here was no statistically significant difference in efficacy between SDZ RA D and sirolimus, Conclusion. SDZ RAD, in the absence of any other immunosuppressant and at d oses that do not show any overt toxicity, considerably prolongs rejection-f ree survival of cynomolgus monkeys after life-supporting kidney allotranspl antation.