There are two commercially available mTOR inhibitors Food and Drug Administration (FDA)-approved in the United States: sirolimus and everolimus. Sirolimus (Rapamune, rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island . Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. In April 2010 everolimus (Zortress), an analog of sirolimus and macrolide immunosuppressive agent, was approved by the FDA.
The pharmacology of the mTOR inhibitors and their use and efficacy in renal transplant recipients will be reviewed here. A discussion of immunosuppressive therapy in renal transplant recipients is presented separately. (See "Maintenance immunosuppressive therapy in renal transplantation in adults".)
MECHANISM OF ACTION
Following entry into the cytoplasm, sirolimus and everolimus bind to the FK binding protein and presumably modulate the activity of the mTOR . The mTOR inhibits interleukin-2 (IL-2)-mediated signal transduction, resulting in cell-cycle arrest in the G1-S phase [2,3]. Sirolimus and everolimus block the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation; in contrast, tacrolimus and cyclosporine inhibit the production of cytokines .
Sirolimus also appears to inhibit proliferation of smooth muscle cells , and, since there is activation of the sirolimus target in tuberous sclerosis lesions, may dampen the growth of angiomyolipomas with tuberous sclerosis . Sirolimus may also have anti-malignancy potential. In March 2009, everolimus (Afinitor) received approval for treatment of advanced renal cell carcinoma. (See "Development of malignancy following solid organ transplantation".)
Peak concentration — The time to peak concentration of sirolimus and everolimus is one to two hours .