mTOR Inhibitors

Mechanistic target of rapamycin (mTOR) inhibitors block T cell proliferation and growth signalling. Sirolimus (rapamycin) and everolimus are used in transplantation to reduce calcineurin inhibitor exposure and in oncology and tuberous sclerosis. They are not nephrotoxic in the way calcineurin inhibitors are, but cause wound healing problems, proteinuria, mouth ulcers and hyperlipidaemia.

Mechanism. Sirolimus and everolimus bind FKBP12, and the complex inhibits mTOR complex 1, blocking progression from G1 to S phase after interleukin 2 signalling. They also reduce vascular smooth muscle proliferation and tumour growth.

Pharmacokinetics. Oral, variable absorption; CYP3A4 and P-glycoprotein substrates; half-life about 60 hours for sirolimus and 30 hours for everolimus; levels measured in whole blood.

Sirolimus.

• Transplant: loading dose 6 mg, then 2 mg daily; target trough 5 to 15 ng/mL (lower with calcineurin inhibitor).
• Lymphangioleiomyomatosis: 2 mg daily to trough 5 to 15 ng/mL.
• Vascular anomalies: low dose with level monitoring.
• Topical form for facial angiofibromas in tuberous sclerosis.

Everolimus.

• Transplant: 0.75 mg twice daily with reduced ciclosporin; trough 3 to 8 ng/mL.
• Cancer: 10 mg daily (breast, renal cell, neuroendocrine tumours).
• Tuberous sclerosis (subependymal giant cell astrocytoma, seizures): 4.5 mg/m2 daily, to a trough 5 to 15 ng/mL.

Timing. Start sirolimus after wound healing (about 4 to 6 weeks after transplant) to avoid dehiscence.

• First-line. Not first-line in usual transplant regimens; used as a conversion from calcineurin inhibitors.
• Alternative. Renal-sparing regimens in kidney and liver transplant; patients with skin cancers after transplant; calcineurin inhibitor nephrotoxicity.
• Specialist. Lymphangioleiomyomatosis, tuberous sclerosis complex, vascular malformations, selected cancers (everolimus), coronary stents (drug-eluting).
• Emergency. None.

Selection. Consider in transplant recipients with recurrent skin cancer, calcineurin inhibitor toxicity or chronic allograft nephropathy. Avoid within the first month after surgery, in nephrotic range proteinuria and in advanced lung disease.

Contraindications. Hypersensitivity; early post-transplant period (liver transplant: first 30 days; lung transplant: bronchial dehiscence risk); proteinuria over 1 g daily (relative); pregnancy.

Serious adverse effects.

• Impaired wound healing, lymphocele, incisional hernia.
• Proteinuria, hyperlipidaemia (triglycerides and cholesterol), peripheral oedema.
• Mouth ulcers, pneumonitis, cytopenias, delayed graft function.
• Infection; diabetes; interstitial lung disease.

Major interactions. CYP3A4 and P-glycoprotein inhibitors (azoles, macrolides, diltiazem, ciclosporin) raise levels; inducers (rifampicin, carbamazepine, phenytoin, St John’s wort) lower levels; ACE inhibitors (angioedema); live vaccines.

Common prescribing errors.

• Starting too early after surgery.
• Not adjusting dose for interacting drugs.
• Skipping lipid and urine protein monitoring.
• Missing pneumonitis (dry cough, breathlessness).
• Continuing through major surgery.

Special groups.

• Pregnancy: avoid; effective contraception during and for 12 weeks after treatment.
• Breastfeeding: avoid.
• Children: specialist dosing by surface area.
• Older adults: monitor infections and lipids.
• Kidney: monitor proteinuria; no dose adjustment for the drug.
• Liver: reduce dose in impairment.
• East Africa: rifampicin lowers levels sharply; check hepatitis B, HIV and tuberculosis status; trough levels need laboratory access, so use only where monitoring is available; treat hyperlipidaemia.

Monitoring. Trough levels at 5 to 7 days after any dose change, then every 1 to 3 months; lipids, urine protein, creatinine, blood count, glucose; chest symptoms; mouth examination; wound status.

Referral and escalation. New breathlessness or cough (pneumonitis); heavy proteinuria; wound complication; severe oedema; infection.

Comparison with alternative classes. mTOR inhibitors spare the kidney and reduce skin cancer risk compared with calcineurin inhibitors, but have more wound, lipid and proteinuria problems and slower tolerability. Antimetabolites and belatacept are other renal-sparing options.