Sirolimus Education

Sirolimus, also called rapamycin, is a macrolide antibiotic extracted from the fungus, Streptomyces hygroscopicus. The drug, which is structurally similar to tacrolimus, received U.S. Food and Drug Administration (FDA) approval in 1999 for the prevention of kidney transplant rejection, in combination with cyclosporine (CsA) and corticosteroids.1

Mechanism of Action
Sirolimus (SRL) forms a complex with an intracellular receptor, immunophilin (FK506-BP), and inhibits the mammalian target of rapamycin (mTOR), a protein kinase, which plays a key role in cytokine-induced cell proliferation. The inhibition further prevents the progression of the cell cycle and blocks the T-cell proliferation, resulting in immunosuppression.2, 3

Clinical Indications1
Sirolimus is commonly used for the following:3

  • Immunosuppression following transplantation
  1. Preventing kidney transplant rejection, in combination with calcineurin inhibitors such as cyclosporine
  2. Ongoing acute rejection
  3. In patients whom calcineurin inhibitors are contraindicated or not tolerated (in combination with steroids)4
  4. As an alternative to mycophenolate mofetil (MMF) when MMF is not well tolerated due to its hematologic and gastrointestinal side effects
  5. For primary therapy if the use of CNIs increase the risk of disease recurrence in patients with hemolytic uremic syndrome (HUS)
  • As a coating on stents to reduce restenosis after cardiac procedures by preventing neo-intimal proliferation


Adverse Effects5

  • Dose-related side effects: Hypercholesterolemia, hypertriglyceridemia, and thrombocytopenia
  • Renal and metabolic abnormalities: Hypophosphatemia, hyperkalemia, peripheral edema, and weight gain
  • Respiratory system disorders: Upper respiratory infection, dyspnea, and pharyngitis
  • Other side effects: Anemia, leucopenia, hypertension, diarrhea, arthralgia, post-transplant lymphoproliferative disorder, fever, rashes, and tremors


Drug Interactions2
Sirolimus administration can result in potentially hazardous interactions if it is administered with other drugs that are metabolized or transported by the same glycoprotein (P-glycoprotein) as sirolimus.6


Substances that increase Siro levels

Substances that decrease Siro levels

Antibacterials: clarithromycin and telithromycin

Antibacterials: rifamycin and rifabutin

Antifungals: ketaconazole, itraconazole, miconazole


Antivirals: lopinavir and atazanavir


Calcium channel blockers: diltiazem


Other immunosuppressants: cyclosporine, mycophenolic acid


Others: Grapefruit juice


Dosage and Administration4
Sirolimus is administered orally at a maintenance dose of 2 mg daily, after an initial loading dose of 6 mg in patients with normal renal function. The co-administration of cyclosporine with sirolimus necessitates a gap of 4 hours between the two drugs to decrease the risk of interaction.

Monitoring of Sirolimus Levels1
The metabolic pathways of sirolimus and other immunosuppressive drugs are similar, necessitating the close monitoring of the drug. The therapeutic drug monitoring (TDM) methods generally followed for sirolimus monitoring include:

  • Trough level concentration (C0) monitoring
  • Area under the curve (AUC) monitoring

The key points to note while monitoring sirolimus concentrations are:

  • Recipients with standard risk of rejection need to maintain therapeutic blood levels at 5-15 ng/mL.
  • Due to inter- and intra-patient variability in trough sirolimus levels, AUC monitoring would be required to adjust the dose.
  • After a dose change, drug concentrations take a long period to reach a steady state. Hence, trough levels after >5-7 days should be performed and dose adjusted accordingly.

Advantages of Sirolimus Therapy

  • A combination of sirolimus and steroid therapy initiated 2 months after transplantation, along with the gradual withdrawal of CsA, improves the calculated glomerular filtration rate at 12 months, and lowers the incremental risk of acute rejection.7

Enduring Expertise for Your Immunosuppressant Drug Testing Needs
With recognized drug testing expertise, Siemens Healthcare Diagnostics offers multiple solutions to meet the sirolimus testing needs of customers in any setting.

Learn more about the sirolimus assays available on the following instruments:

1. Dupont P, et al. The evolving role of sirolimus in renal transplantation. Q J Med. 2003;96:401-409. Link
2. Jacobs CN, et al. Little Black Book of Nephrology and Hypertension. Jones & Bartlett Publishers;2008:320. Link
3. Khan MM. Immunopharmacology. Springer;2008:94. Link
4. Ashley C, et al. The Renal Drug Handbook. Radcliffe Publishing;2008:671. Link
5. Anderson PO, et al. Handbook of Clinical Drug Data. McGraw-Hill Professional;2001:285. Link
6. Brunton LL, et al. Goodman and Gilman's Manual of Pharmacology and Therapeutics. McGraw-Hill Professional;2007:915. Link
7. Kreis H., et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol. 2004:15:809-817 Link