Sirolimus

Sirolimus is a macrolide mTOR inhibitor used for prophylaxis of rejection in kidney transplantation, often to spare or replace a calcineurin inhibitor, and for lymphangioleiomyomatosis. It has no direct nephrotoxicity but causes wound healing problems, hyperlipidaemia and proteinuria, and requires trough monitoring.

Class. mTOR (mechanistic target of rapamycin) inhibitor, proliferation signal inhibitor.

Mechanism. It binds FKBP12, and the complex inhibits mTOR complex 1, blocking interleukin 2 driven T and B cell proliferation at the G1 to S transition. It also has antiproliferative effects on vascular smooth muscle and tumour cells.

Pharmacokinetics. Oral bioavailability is about 14 percent and is raised by high fat meals. Metabolised by CYP3A4 and a P-glycoprotein substrate. The half-life is about 62 hours, so steady state takes 5 to 7 days and dose changes should not be repeated sooner than 7 to 14 days.

Kidney transplantation, low to moderate immunological risk (with ciclosporin then withdrawal).

• Loading dose: 6 mg orally as a single dose, as soon as possible after transplant.

• Maintenance dose: 2 mg once daily.

• Titration: adjust to a trough of 4 to 12 ng/mL while on ciclosporin; if ciclosporin is withdrawn at 2 to 4 months, raise the trough target to 12 to 20 ng/mL for the first year, then 10 to 15 ng/mL.

• Maximum dose: no fixed ceiling; set by trough and toxicity .

Kidney transplantation, high risk (with ciclosporin and a glucocorticoid). Loading dose up to 15 mg, then 5 mg daily with trough targeted to 10 to 15 ng/mL for the first year.

Conversion from calcineurin inhibitor (late conversion, specialist). Start 3 to 5 mg daily without a loading dose, increase to the target trough over 2 to 4 weeks.

Lymphangioleiomyomatosis. 2 mg once daily, adjusted to a trough of 5 to 15 ng/mL, with monitoring of lung function.

Hepatic impairment. Reduce the maintenance dose by about one third in mild to moderate impairment and by about one half in severe impairment; the loading dose is not changed.

Children (13 years and over, under 40 kg). Loading dose 3 mg/m2, maintenance 1 mg/m2 once daily.

Contraindications. Hypersensitivity to sirolimus or components. Avoid in lung transplantation (bronchial anastomotic dehiscence) and in liver transplantation within the first 30 days (hepatic artery thrombosis).

Boxed-warning-level risks. Immunosuppression with infection and lymphoma and skin cancer, hepatic artery thrombosis in liver transplantation, excess mortality and bronchial anastomotic dehiscence in lung transplantation, and renal function decline when combined with full dose ciclosporin.

Adverse effects. Common: hyperlipidaemia, peripheral oedema, mouth ulcers, acne, anaemia, thrombocytopenia, arthralgia, raised creatinine in combination. Serious: non-infectious pneumonitis, proteinuria and nephrotic syndrome, impaired wound healing and lymphocele, thrombotic microangiopathy with calcineurin inhibitors, venous thromboembolism, angioedema with ACE inhibitors, male infertility, new-onset diabetes.

Major interactions. Strong CYP3A4 or P-glycoprotein inhibitors (ketoconazole, voriconazole, clarithromycin, ritonavir; avoid) and inducers (rifampicin, carbamazepine, phenytoin, St John's wort; avoid), ciclosporin (give sirolimus 4 hours after), grapefruit, ACE inhibitors (angioedema), live vaccines (avoid), and other myelosuppressives.

Common prescribing errors. Starting early after surgery without considering wound healing; changing the dose before steady state; missing interacting azoles; omitting lipid and urine protein checks.

Special groups.

• Pregnancy: avoid; use effective contraception during treatment and for 12 weeks afterwards.

• Breastfeeding: avoid.

• Older adults: no specific adjustment; closer infection monitoring.

• Kidney impairment: no adjustment, but proteinuria must be followed.

• Liver impairment: reduce maintenance by about one third in mild to moderate and one half in severe impairment.

• Region: screen for hepatitis B, HIV and latent tuberculosis; trough monitoring may be limited, so confirm assay availability before choosing the drug.

Formulations. 0.5, 1 and 2 mg tablets and 1 mg/mL oral solution. Take at the same time each day, consistently with or without food, and 4 hours after ciclosporin. Do not crush tablets.

Baseline. Full blood count, creatinine, lipid profile, urine protein to creatinine ratio, liver enzymes, hepatitis and HIV serology, and tuberculosis assessment.

Monitoring. Whole blood trough 7 to 14 days after each dose change, then at each clinic visit. Lipids at 4 to 8 weeks and 3 monthly. Urine protein, full blood count and creatinine each clinic visit. Pneumocystis prophylaxis for 6 to 12 months after transplant.

Stop or switch thresholds. Sustained urine protein over 1 g daily; non-infectious pneumonitis; severe wound dehiscence; refractory hyperlipidaemia; thrombotic microangiopathy.

Referral and escalation. Always transplant specialist initiated. Refer for new cough with infiltrates, rising proteinuria, or wound complications.