History

• Originally Isolated from the Streptomyces Hygroscopicus Bacteria from a Soil Sample from Easter Island (Island is Also Known as Rapa Nui)

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Indications

Transplantation

• Anti-Rejection in Solid Organ Transplant

TSC-Related Disorders

• Lymphangioleiomyomatosis (LAM) (see Lymphangioleiomyomatosis, [[Lymphangioleiomyomatosis]])
  • MILES Trial (NEJM, 2011) [MEDLINE]
  • Generally, max of 2 mg/day (does above this may have more toxicity without additional clinical benefit)
  • Monitor sirolimus levels (aim for trough level: 5-15 ng/mL)
  • Monitor fasting lipids, glucose, blood counts, liver function, renal function, and urine protein after the first month of therapy and then, q3-6 mo
• Tuberous Sclerosis (see Tuberous Sclerosis, [[Tuberous Sclerosis]])

Other

• Stent-Coating Agent
  • Coronary Stents

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Pharmacology

• Mechanistic Target of Rapamycin (mTOR) Inhibitor (see Mechanistic Target of Rapamycin Inhibitors, [[Mechanistic Target of Rapamycin Inhibitors]]): unlike tacrolimus, sirolimus is not a calcineurin inhibitor
  • Antiproliferative Properties
  • Immunosuppressive Properties
  • Inhibits Response to IL-2 -> blocks activation of T- and B-cells

Metabolism

• xxx

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Administration

• PO

Dose Adjustment

• Hepatic
• Renal

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Adverse Effects

Dermatologic Adverse Effects

• Acneiform Rash
• Delayed Wound Healing

Endocrinologic Adverse Efefcts

• Hypercholesterolemia (see xxxx, [[xxxx]])
• Hypertriglyceridemia (see Hypertriglyceridemia, [[Hypertriglyceridemia]])

Infectious Adverse Effects

• Increased Risk of Infection

Gastrointestinal Adverse Effects

• Diarrhea (see xxxx, [[xxxx]])
• Mucositis
• Nausea (see xxxx, [[xxxx]])

Neurologic Adverse Effects

• Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]])

Pulmonary Adverse Effects

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])

• Epidemiology:

Subacute Interstitial Pneumonitis (see Interstitial Lung Disease, [[Interstitial Lung Disease]])

• Epidemiology:
• Treatment: usually resolves with discontinuation of sirolimus

Cryptogenic Organizing Pneumonia (COP) (see Cryptogenic Organizing Pneumonia, [[Cryptogenic Organizing Pneumonia]])

• Epidemiology:
• Treatment: typically resolves with discontinuation of sirolimus

Pulmonary Alveolar Proteinosis (see Pulmonary Alveolar Proteinosis, [[Pulmonary Alveolar Proteinosis]])

• Epidemiology: case reports
• Treatment: typically resolves with discontinuation of sirolimus

Granulomatous Lung Disease (see Granulomatous Lung Disease, [[Granulomatous Lung Disease]])

• Epidemiology: case reports
• Treatment: typically resolves with discontinuation of sirolimus

Diffuse Alveolar Hemorrhage (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])

• Epidemiology:
• Treatment: typically resolves with discontinuation of sirolimus

Renal Adverse Effects

• Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): when used in combination with cyclosporine A, sirolimus + cyclosporine had higher Cr than cyclosporine alone
• Proteinuria (see xxxx, [[xxxx]])

Rheumatologic Adverse Effects

• Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]])

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References

• Sirolimus-associated pulmonary toxicity. Transplantation. 2004 Apr 27;77(8):1215-20
• Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis. 2010 Feb;55(2):335-43. Epub 2009 Nov 17
• Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? Respir Res. 2011;12:66. Epub 2011 May 21 [MEDLINE]
• MILES Trial. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595-1606 [MEDLINE]
• Current management of lymphangioleiomyomatosis. Curr Opin Pulm Med. 2011 Sep;17(5):374-8. doi: 10.1097/MCP.0b013e328349ac8c [MEDLINE]