Sirolimus

Structure of sirolimus. Source: Wikimedia Commons

It belongs to a class of antibiotics and immunosuppressive drugs known as macrolides, all of which share a large lactone ring to which are attached one or more deoxy sugars. A more famous immunosuppressive member of this family is tacrolimus (marketed as Protopic); other macrolides used as antibiotics include erythromycin, clarithromycin, and azithromycin. It was approved by the FDA in August, 2000.

Sirolimus is also used in some types of cardiac stents as a coating around the expandable metal mesh; its properties may provide advantages over the bare-metal type of stent.

Other Names

Sirolimus is marketed by Wyeth as Rapamune and was previously known as rapamycin.

Uses

Sirolimus is used to prevent organ rejection in patients receiving kidney transplants. It is indicated for use in patients 13 years of age and older.

Depending on the particular patient, sirolimus may be given along with cyclosporine and corticosteroids.

How Sirolimus is Taken

Sirolimus is avaiable as an oral solution at a concentration of 1 mg/mL (60 mg in 60 mL) and as tablets containing 1, 2, or 5 mg active ingredient. It is taken once daily, and the initial dose should be administered as soon as possible after transplantation. If sirolimus is given with cyclosporine, it is recommended that sirolimus be taken four hours after administration of cyclosporine.

How Sirolimus Works

Sirolimus enters T-lymphocytes - the white blood cells responsible for organ rejection. It then binds to a protein called FK Binding Protein-12 (FKBP-12) and generates a immunosuppressive complex. This complex binds to and inhibits the activation of an enzyme called mTOR, a key regulatory kinase. This inhibition of mTOR suppresses T-cell proliferation and, in turn, reduces the severity of organ rejection.

How the Body Affects Sirolimus

Sirolimus is rapidly absorbed, with peak circulating levels reached at approximately two hours after multiple doses in kidney transplant recipients. The drug is metabolized by the liver enzyme CYP3A4 and P-glycoprotein (P-gp) in the lining of the gut. About 91% of the original dose is excreted as metabolites in the feces, and only a minor amount (~2%) is excreted in the urine.

Side Effects

The most common (≥ 30%) side effects observed with sirolimus in clinical studies are:

• peripheral edema (fluid retention/swelling in the limbs)
• hypertriglyceridemia (high blood lipid levels)
• hypertension
• hypercholesterolemia (high blood cholesterol levels)
• increased blood creatinine levels
• constipation
• abdominal pain
• diarrhea
• headache
• fever
• urinary tract infection
• anemia (low red blood cell counts or hemoglobin levels)
• nausea
• arthralgia (joint aches)
• pain
• thrombocytopenia (low blood platelet counts)

Risks and Precautions

Increased susceptibility to infection and lymphoma

Increased susceptibility to infection and the development of lymphoma may result from immunosuppression with sirolimus.

Liver transplantation

The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in liver transplant patients.

The use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT (hepatic artery thrombosis or "clotting of the artery feeding the liver"); most cases of HAT occurred within one month post-transplant and most led to graft loss or death.

Lung transplantation

Fatal cases of bronchial anastomotic dehiscence (breakdown of the surgical connections in the lung's airways) have been reported in lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.^[1]

Hypersensitivity reactions

Hypersensitivity (allergic) reactions have been associated with the administration of sirolimus.

Skin cancer

There is an increased risk for skin cancer when taking sirolimus. Exposure to sunlight is to be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Pregnancy

It is recommended that women of childbearing age use effective contraception prior to initiation of sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped.

Drug Interactions

Other drugs that interact with CYP3A4 and P-gp

Sirolimus is known to be a substrate for the liver enzyme CYP3A4 and P-gp in the gut lining. Other drugs processed by CYP3A4 and P-gp include:

• cyclosporine
• rifampin
• rifabutin
• ketoconazole
• voriconazole
• itraconazole
• fluconazole
• erythromycin
• telithromycin
• clarithromycin
• bromocriptione
• cimetidine
• cisapride
• clotrimazole
• danazol
• diltiazem
• HIV-protease inhibitors (e.g., ritonavir, indinavir)
• metoclopramide
• nicardipine
• troleandomycin
• verapamil
• carbamazepine
• phenobarbital
• phenytoin
• rifapentine
• St. John's Wort (Hypericum perforatum)

Grapefruit juice

Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it should not be taken with sirolimus or be used for dilution of sirolimus.

Vaccination

Immunosuppressants may affect response to vaccination. The use of live vaccines should be avoided, such as:

• measles, mumps, rubella (MMR)
• oral polio
• BCG
• yellow fever
• varicella
• TY21a typhoid

Effectiveness

Phase I, II, and III trials of sirolimus are now complete and have demonstrated sirolimus to be effective in the prevention of acute organ rejection following kidney transplant.^[2]

References

1. ↑ King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation. 2003 May 15;75(9):1437-43. Abstract
2. ↑ Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation. 1999;68:1526-1532. Abstract

External Links

FDA: Rapamune Patient Information Sheet