Effect of tacrolimus (FK506) and sirolimus (rapamycin) mono- and combination therapy in prolongation of renal allograft survival in the monkey

Background. Our previous studies confirmed that tacrolimus (FK506) and siro limus [rapamycin (RAPA)], in combination, are not antagonistic but are syne rgistic in the prolongation of heart and small bowel grafts in the rodent. The aim of this study was to confirm further the synergistic effect of comb ined FK506 and RAPA in the more clinically relevant model, kidney transplan tation in monkeys. Methods. A total of 60 male Vervet monkeys were randomly assigned to 10 gro ups (n greater than or equal to 5). Monkeys with renal allografts were trea ted with different doses of FK506 and/or RAPA orally for 60 days. Graft sur vival, body weight, clinical biochemistry determinations, oral glucose tole rance test, trough levels of the two drugs, and histopathology were investi gated. Results. Low doses of FK506 (1 or 4 mg/kg) combined with RAPA (0.5 mg/kg) p roduced synergistic effect in the prolongation of renal graft survival [com bination index (CI)=0.292, 0.565]. There were no additive or synergistic dr ug-associated toxicities such as hyperglycemia, nephrotoxicity, and hyperli pidemia. There also was no pharmacological antagonism. Conclusion. Concomitant therapy of low-dose (drug-optimal) FK506 and RAPA p roduced a synergistic effect in the prolongation of kidney allograft surviv al in Vervet monkeys without additive drug-associated toxicities.