Bd. Kahan et al., IMMUNOSUPPRESSIVE EFFECTS AND SAFETY OF A SIROLIMUS CYCLOSPORINE COMBINATION REGIMEN FOR RENAL-TRANSPLANTATION/, Transplantation, 66(8), 1998, pp. 1040-1046
Background. Sirolimus, a novel immunosuppressant that inhibits cytokin
e-driven. cell proliferation and maturation, prolongs allograft; survi
val in animal models. After a phase I trial in stable renal transplant
recipients documented that cyclosporine and sirolimus have few overla
pping toxicities, we conducted an open-label, single-center, phase I/I
I dose-escalation trial to examine the safety and efficacy of this dru
g combination. Methods. Forty mismatched living-donor renal transplant
recipients were sequentially assigned to receive escalating initial d
oses of sirolimus (0.5-7.0 mg/m(2)/day), in addition to courses of pre
dnisone and a concentration-controlled regimen of cyclosporine. We con
ducted surveillance for drug-induced side effects among sirolimus-trea
ted patients and compared their incidence of acute rejection episodes
as well as mean laboratory values with those of a historical cohort of
65 consecutive, immediately precedent, demographically similar recipi
ents treated with the same concentration-controlled regimen of cyclosp
orine and tapering doses of prednisone. Results. The addition of sirol
imus reduced the overall incidence of acute allograft; rejection episo
des to 7.5% from 32% in the immediately precedent cyclosporine/prednis
one-treated patients, At 18- to 47-month follow-up periods, both treat
ment groups displayed similar rates of patient and graft survival, as
well as morbid complications. Although sirolimus-treated patients disp
layed comparatively lower platelet and white blood cell counts and hig
her levels of serum. cholesterol and triglycerides, sirolimus did not
augment the nephrotoxic or hypertensive proclivities of cyclosporine.
The degree of change in the laboratory values was more directly associ
ated with whole blood trough, drug concentrations than with doses of s
irolimus. Conclusions. Sirolimus potentiates the immunosuppressive eff
ects of a cyclosporine-based regimen by reducing the rate of acute rej
ection episodes.