Sirolimus: a new agent for prevention of renal allograft rejection

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of sirolimus are reviewed. Sirolimus can be used as an adjunct to cyclosporine and corticosteroids for preventing organ rejection in renal allograft recipients. It appears to block cell-cycle progression in the mid-to-late G1 phase; it also inhibits interleukin-2-dependent and independent proliferation of B-lymphocytes and production of immunoglobulins A, M, and G. Sirolimus is extensively metabolized by the liver and undergoes O-demethylation and hydroxylation. The mean oral clearance is 208 +/- 95 mL/hr/kg with an elimination half-life of 57 to 63 hours in kidney transplant recipients. Sirolimus is poorly absorbed from the gastrointestinal tract; its apparent oral bioavailability is about 15%. Two pivotal Phase III, multicenter, randomized, double-blind trials evaluating the efficacy of sirolimus in the prophylaxis of acute renal allograft rejection after transplantation have been conducted. A significant reduction in the occurrence of acute rejection was noted in both trials compared with azathioprine- or placebo-treated patients. Also, both sirolimus groups required significantly less antibody therapy for treatment of rejection. The primary adverse effects associated with sirolimus therapy include hypercholesterolemia and hypertriglyceridemia. Hypertension, diarrhea, increased creatinine, hypokalemia, arthralgia, rash, acne, leukopenia, and thrombocytopenia have also been observed. The labeled recommendations are a 6-mg loading dose as soon as possible after transplantation and a maintenance dose of 2 mg per day. Sirolimus is a potent novel immunosuppressive agent with proven efficacy in the prevention of acute rejection after renal transplantation. Use of sirolimus may lead to effective therapeutic strategies for sparing the use of cyclosporine and corticosteroids.