Toxicity and efficacy of sirolimus: Relationship to whole-blood concentrations

Background: Sirolimus is a novel macrolide immunosuppressive drug with a mechanism of action distinct from that of both cyclosporine and tacrolimus. Recent clinical studies have demonstrated a decrease in acute rejection episodes in renal transplant patients receiving sirolimus compared with controls. The major toxicities associated with sirolimus treatment are thrombocytopenia and hyperlipidemia. In addition, concern has been raised by the higher serum creatinine levels noted in patients receiving sirolimus and cyclosporine compared with controls receiving cyclosporine and azathioprine. Objective: The objective of the present review is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. Results: The literature indicates that trough concentrations of sirolimus >15 ng/mL appear to be associated with a greater risk of both thrombocytopenia and hyperlipidemia, whereas trough sirolimus concentrations <6 ng/mL have been associated with an increased incidence of acute rejection. Conclusion: The evidence to date supports target trough sirolimus concentrations of 6 to 15 ng/mL in most patients. In higher-risk groups and patients receiving cyclosporine-sparing regimens, higher concentrations may be necessary to achieve similar efficacy.