Tacrolimus

Tacrolimus is a macrolide calcineurin inhibitor and the usual first-line maintenance drug in kidney, liver, heart and lung transplantation. It is more potent than cyclosporine on a weight basis, is used off label in lupus nephritis and other autoimmune disease, and requires level monitoring because of its narrow therapeutic window.

Class. Calcineurin inhibitor immunosuppressant.

Mechanism. It binds FK506-binding protein 12, and the complex inhibits calcineurin, blocking interleukin 2 transcription and T cell activation.

Pharmacokinetics. Absorption is variable and reduced by food (bioavailability about 25 percent). Metabolised by CYP3A4 and CYP3A5 and a P-glycoprotein substrate. Half-life about 12 hours for the immediate release form and about 35 hours for prolonged-release. Most patients of African ancestry express functional CYP3A5, which lowers levels and often calls for higher doses, directed by early trough levels.

Kidney transplantation (adult).

• Immediate release: 0.1 to 0.2 mg/kg/day orally in 2 divided doses, started within 24 to 48 hours of surgery.

• Prolonged-release: 0.15 to 0.2 mg/kg once daily.

• Intravenous: 0.01 to 0.05 mg/kg/day by continuous infusion if oral route is not possible.

• Trough target: 8 to 12 ng/mL in the first 3 months, then 5 to 8 ng/mL (varies with the combination used).

• Loading dose: none as a bolus; first dose is the weight-based dose.

Liver transplantation. 0.10 to 0.20 mg/kg/day orally in 2 divided doses; trough target 5 to 10 ng/mL after the early period.

Heart transplantation. 0.075 mg/kg/day orally in 2 divided doses; trough target 8 to 15 ng/mL early, then 5 to 10 ng/mL.

Lupus nephritis (off label, specialist; multitarget or add-on regimen). Often 0.05 to 0.1 mg/kg/day in 2 divided doses with trough 4 to 7 ng/mL, or fixed 3 to 4 mg daily, alongside a glucocorticoid and mycophenolate.

Maintenance dose. Dose adjusted to trough level; typical long-term dose is about 0.05 to 0.1 mg/kg/day.

Maximum dose. No fixed ceiling; dose is limited by trough level and toxicity.

Conversion between formulations. Do not switch between immediate release and prolonged-release without a planned dose conversion (often 1 to 1 on the total daily dose) and trough check within 1 week.

Contraindications. Hypersensitivity to tacrolimus or macrolides, or polyoxyethylated castor oil in the intravenous form.

Boxed-warning-level risks. Malignancy (lymphoma and skin cancer) and serious infection; use only under transplant specialist supervision.

Adverse effects. Common: tremor, headache, hypertension, nephrotoxicity, hyperkalaemia, hypomagnesaemia, diarrhoea, post-transplant diabetes mellitus. Serious: thrombotic microangiopathy, posterior reversible encephalopathy syndrome, seizures, QT prolongation, BK virus nephropathy, cytomegalovirus infection, post-transplant lymphoproliferative disorder.

Major interactions. Same pattern as cyclosporine. Raised levels: diltiazem, verapamil, azole antifungals, clarithromycin and erythromycin, grapefruit, ritonavir. Lowered levels: rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort. Additive nephrotoxicity with NSAIDs and aminoglycosides, and hyperkalaemia with potassium-sparing diuretics and ACE inhibitors. QT-prolonging drugs add risk. Live vaccines are avoided.

Common prescribing errors. Confusing immediate release and prolonged-release products; failing to check levels after starting or stopping interacting drugs; giving with grapefruit; dosing from a level taken at the wrong time.

Special groups.

• Pregnancy: used in transplant recipients; monitor levels closely because clearance changes, plus blood pressure and glucose.

• Breastfeeding: limited data; infant exposure is low and many centres permit with monitoring.

• Children: higher weight-based doses are usually needed; closer level monitoring.

• Older adults: lower starting doses and closer monitoring.

• Kidney impairment: no clearance adjustment; nephrotoxicity limits dose.

• Liver impairment: reduce the dose (often by one third to one half) and monitor levels.

• Region: in East Africa and other populations of African ancestry, expect to need higher doses and earlier levels; availability of level monitoring should be confirmed before starting.

Formulations. Immediate release capsules (0.5, 1 and 5 mg) twice daily at consistent times; prolonged-release capsules once daily in the morning; intravenous concentrate (dilute in 0.9 percent sodium chloride or 5 percent glucose; use non-polyvinyl chloride containers). Take on an empty stomach or consistently relative to food, and avoid grapefruit.

Baseline. Creatinine and eGFR, potassium, magnesium, glucose, liver enzymes, blood pressure, and an electrocardiogram if QT-prolonging drugs are used.

Monitoring. 12 hour trough whole blood level 2 to 3 days after starting or changing dose or interacting drugs, then at least weekly in the early period, monthly in the first year, then every 3 months. Creatinine, potassium, glucose and blood pressure at each visit.

Stop or reduce thresholds. Trough over target with tremor, neurotoxicity or creatinine rise: reduce or hold. Thrombotic microangiopathy or posterior reversible encephalopathy syndrome: stop or switch.

Overdose. No antidote. Supportive care, activated charcoal if early; haemodialysis is not effective.

Referral and escalation. Always specialist initiated. Refer urgently for acute graft dysfunction, neurological symptoms, or levels outside target.