Sirolimus-based immunosuppression: present state of the art

Abstract

Sirolimus, a macrocyclic lactone with a novel mechanism of action, augments acute rejection prophylaxis when administered in combination with cyclosporine (CsA) and steroids and seems to reduce the occurrence and progression of chronic vascular obliterative processes. Although clinical studies in psoriasis patients suggest that sirolimus is not nephrotoxic, the drug does show a range of toxic side effects, including altered lipid metabolism, myelosuppression, arthropathy, and impaired wound healing. Our experience with 1008 renal transplant patients who were administered sirolimus demonstrates that through careful therapeutic drug monitoring, it is possible to maximize the benefits and minimize the hazards of chronic immunosuppression with a sirolimus-based regimen. While sirolimus was initially introduced as an adjunctive agent to calcineurin inhibitors, it now serves as the base for therapies that spare the exposure to these nephrotoxic drugs. However, to optimize the use of sirolimus as base therapy, further work is necessary to determine appropriate target concentrations over time, the requirement for concomitant steroids and/or nucleoside synthesis blockers, and the best countermeasure strategies to overcome the drug's adverse effects.