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
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.