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Sirolimus (also known as rapamycin) is a macrocyclic lactone-based mTOR (mammalian target of rapamycin) inhibitor that is used for the prevention of graft rejection in solid organ transplant patients.1 It is currently approved for use in renal transplant patients. It is also used to prevent rejection in other solid organ transplant recipients as well as the treatment of graft-versus-host disease in hematopoietic stem cell transplant patients.1,2 The immunomodulating properties of sirolimus are due to its ability to block the effects of interleukin-2 on T-lymphocyte activation and proliferation.1,3 Sirolimus binds to FK-binding protein-12 (FKPB-12), an intracellular cytoplasmic protein found in T cells. The sirolimus-FKPB complex then binds to mTOR, which inhibits the reaction of the T cell to interleukin-2 binding to its outer cell wall. This action prevents T-cell proliferation and progression of the cell cycle.

Because the calcineurin inhibitors (cyclosporine and tacrolimus) are nephrotoxic, sirolimus is used by many transplant centers as part of calcineurin inhibitor avoidance regimens or calcineurin inhibitor conversion protocols in order to avoid drug-induced renal damage.1,2,4


The therapeutic range of sirolimus used by clinicians varies greatly according to the type of assay used to measure the drug.5,6,7, and 8 For the purposes of the pharmacokinetic calculations and problems presented in this book, sirolimus concentrations in the blood using a sirolimus-specific chromatograph assay methodology will be used, and the therapeutic range for steady-state sirolimus concentrations of 5-15 ng/mL will be assumed to be appropriate. For renal transplant patients, sirolimus concentrations <5 ng/mL are associated with acute rejection episodes and sirolimus concentrations >15 ng/mL are related to the development of adverse effects.9

Desired sirolimus concentrations differ between the various types of transplants, change with time during the posttransplantation phase, and are determined by protocols specific to the transplantation service and institution where the patient is treated.1,2,4,8 It is very important for clinicians to be aware of these factors since acceptable sirolimus concentrations under various circumstances may be different than those given by a specific clinical laboratory or those suggested in this textbook.

For patients receiving solid organ transplants, the goal of sirolimus therapy is to prevent acute or chronic rejection of the transplanted organ while minimizing drug side effects.1,10,11,12, and 13 In this case, the recipient’s immune system detects foreign antigens on the donor organ which produces an immunologic response against the graft. This leads to inflammatory and cytotoxic effects directed against the transplanted tissue, and produces the risk of organ tissue damage and failure. In the case of a rejected kidney transplant, it is possible to remove the graft and place the patient on a form of dialysis to sustain their life. However, for other solid organ transplantation patients, graft rejection can result in death.


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