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 sirolimus [rapamycin (RAPA)], in combination, are not antagonistic but are synergistic 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 combined FK506 and RAPA in the more clinically relevant model, kidney transplantation in monkeys.


METHODS
A total of 60 male Vervet monkeys were randomly assigned to 10 groups (n> or =5). Monkeys with renal allografts were treated with different doses of FK506 and/or RAPA orally for 60 days. Graft survival, body weight, clinical biochemistry determinations, oral glucose tolerance test, trough levels of the two drugs, and histopathology were investigated.


RESULTS
Low doses of FK506 (1 or 4 mg/kg) combined with RAPA (0.5 mg/kg) produced synergistic effect in the prolongation of renal graft survival [combination index (CI) = 0.292, 0.565]. There were no additive or synergistic drug-associated toxicities such as hyperglycemia, nephrotoxicity, and hyperlipidemia. There also was no pharmacological antagonism.


CONCLUSIONS
Concomitant therapy of low-dose (drug-optimal) FK506 and RAPA produced a synergistic effect in the prolongation of kidney allograft survival in Vervet monkeys without additive drug-associated toxicities.
Qi
S
S
Laboratories of Experimental Surgery and Transplantation Immunology, University of Montreal, Notre-Dame Hospital, Quebec, Canada.
Xu
D
D
Peng
J
J
Vu
M D
MD
Wu
J
J
Bekersky
I
I
Fitzsimmons
W E
WE
Peets
J
J
Sehgal
S
S
Daloze
P
P
Chen
H
H
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005951:Glucose Tolerance Test; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D020123:Sirolimus / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus