indication

For the prophylaxis of organ rejection in patients receiving renal transplants.

pharmacology

Sirolimus, a macrocyclic lactone produced by Streptomyces hygroscopicus, is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.

mechanism of action

Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.

half life

57-63 hours

drug interactions

Atazanavir: Increases the effect and toxicity of immunosuppressant

Clarithromycin: The macrolide, clarithromycin, may increase the serum concentration of sirolimus.

Cyclosporine: Increases the effect and toxicity of sirolimus

Diltiazem: Increases the effect and toxicity of sirolimus

Erythromycin: The macrolide, erythromycin, may increase the serum concentration of sirolimus.

Fosphenytoin: The hydantoin decreases sirolimus levels

Itraconazole: Itraconazole may increase the effect and toxicity of sirolimus.

Ketoconazole: Ketoconazole may increase the effect and toxicity of sirolimus.

Phenytoin: The hydantoin decreases sirolimus levels

Rifabutin: The rifamycin decreases the effect of sirolimus

Rifampin: The rifamycin decreases the effect of sirolimus

Tacrolimus: Sirolimus may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Sirolimus therapy is initiated, discontinued or altered.

Telithromycin: Telithromycin may reduce clearance of Sirolimus. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sirolimus if Telithromycin is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may affect the efficacy/toxicity of Sirolimus.

Trandolapril: Increased risk of angioedema. Monitor for signs and symptoms of facial and systemic edema and/or erythema.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Voriconazole: Voriconazole may increase the serum concentration of sirolimus likely by inhibition of CYP3A4-mediated metabolism or p-glyprotein transport of sirolimus. Consider alternate therapy or reduce the dose of sirolimus and monitor serum levels during concomitant therapy.