Clinical Information

Sirolimus is a macrolide antibiotic, isolated from Streptomyces hygroscopicus, with potent effects, including suppression of T- and B-cell proliferation and antineoplastic and antifungal activity. It inhibits the protein kinase mTOR (mechanistic target of rapamycin) to arrest the cell cycle; it has no effects on calcineurin and, therefore, can be used in addition to cyclosporine or tacrolimus, or as a substitute in patients intolerant to these drugs.

Sirolimus is metabolized by cytochrome P450 (CYP) 3A4; thus, blood concentrations are affected by drugs that inhibit or induce this enzyme. The pharmacokinetic interaction between sirolimus and cyclosporine or tacrolimus increases both therapeutic immunosuppression and the toxicity of these agents; lower doses are required with combined use. Adverse effects of sirolimus are generally concentration dependent, making therapeutic drug monitoring essential.

The frequency of monitoring trough concentrations varies on the indication. For example, for kidney transplant recipients, sirolimus is commonly measured at least 3 to 4 days after a loading dose or, if the kidney transplant recipient is receiving cyclosporin, between 5 to 7 days after initiation. Target concentrations vary depending on concomitant therapy, time posttransplant, the desired degree of immunosuppression, and adverse effects. When given with cyclosporine or tacrolimus, the therapeutic range for sirolimus is generally between 4 and 12 ng/mL with minimal added benefit for concentrations greater than10 ng/mL. When sirolimus is given without calcineurin inhibitors, higher trough levels are needed, usually 12 to 20 ng/mL, but occasionally up to 20 to 30 ng/mL.