What is Sirolimus (Rapamune)?

From the Guidelines

Sirolimus, also known as rapamycin, is an immunosuppressive medication used to prevent organ rejection in transplant patients, particularly in renal transplants, by inhibiting T-cell proliferation through its binding to FK-binding protein and subsequent inhibition of the mammalian target of rapamycin (mTOR) pathway 1.

Key Characteristics of Sirolimus

• The medication has antiproliferative and antiangiogenic effects, making it potentially useful in the treatment of cancer and attenuation of radiation-induced effects 1.
• Sirolimus is used in cardiac stents to prevent restenosis due to its antiproliferative properties 1.
• It may also affect conditions such as hypertrophic myocarditis, pulmonary fibrosis, hepatic fibrosis, and autosomal-dominant polycystic kidney disease 1.
• Sirolimus has been linked to the treatment of tuberous sclerosis or lymphangioleiomyomatosis (LAM), PTEN (Cowden disease), LKB1 (Peutz-Jeghers syndrome), and NF1 (neurofibromatosis) due to its impact on the mTOR pathway 1.

Clinical Use and Dosage

• The typical oral dose of sirolimus is 2-5 mg per day, administered in combination with other immunosuppressants such as tacrolimus or cyclosporine 1.
• A loading dose is usually given, followed by maintenance doses, with trough levels monitored to maintain a therapeutic range 1.
• Treatment with sirolimus is usually initiated immediately after transplantation and continued indefinitely to maintain immunosuppression 1.

Important Considerations

• Sirolimus carries a FDA black box warning for use in de novo liver transplant recipients due to increased incidence of hepatic artery thrombosis and mortality 1.
• Its use in liver transplantation has been explored, with studies showing potential benefits in reducing renal toxicity but also highlighting the need for careful patient selection and monitoring 1.

From the Research

Definition and Mechanism of Sirolimus

• Sirolimus, also known as rapamycin, is a potent immunosuppressant that blocks cell cycle progression 2.
• It is a mammalian target of rapamycin (mTOR) inhibitor that inhibits cell cycle progression and has proven to be a potent immunosuppressive agent for use in solid organ transplant recipients 3.

Clinical Use of Sirolimus

• Sirolimus is used to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine and corticosteroids 2.
• It can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from cyclosporine 4.
• Sirolimus is also used in solid organ transplantation, including kidney, lung, and other organs, to reduce the incidence of acute rejection and improve graft survival 3, 5.

Adverse Effects of Sirolimus

• The most common adverse effects of sirolimus are hyperlipidaemia and myelosuppression 3.
• Other adverse effects include thrombocytopenia, leukopenia, increased liver enzymes, and hypokalemia 4.
• Sirolimus has also been associated with an increased risk of venous thromboembolism (VTE) in lung transplant recipients 5.
• Postmarketing studies have revealed unforeseen adverse effects, including impaired wound healing, proteinuria, oedema, pneumonitis, and thrombotic microangiopathy 3.

Pharmacokinetics of Sirolimus

• Sirolimus has poor oral absorption and distributes widely in tissues, displaying a wide inter- and intrapatient variability in drug clearance 6.
• The critical role of the cytochrome P450 3A4 system for sirolimus biotransformation leads to extensive drug-drug interactions, among which are increases in cyclosporin concentrations 6.
• Therapeutic drug monitoring is required to minimize drug-related toxicities and maximize efficacy, with a target trough concentration range of 5 to 15 microg/L 6.