Tacrolimus Therapeutic Drug Monitoring

Tacrolimus is a calcineurin inhibitor used in solid organ transplantation, lupus nephritis, refractory nephrotic syndrome and some inflammatory conditions. It has a narrow therapeutic window and wide variability in absorption and metabolism, so dosing is set by whole blood trough levels.

Sampling. Take a trough (pre-dose) blood sample 12 hours (plus or minus 1 hour) after the evening dose and before the morning dose, into an EDTA tube; test results are available within 24 hours. Draw from a different site from the line used for infusion.

Steady state. Levels stabilise 3 to 5 days after any change in dose, formulation or interacting drug; do not adjust before steady state unless toxicity is evident.

Formulations. Immediate-release is taken twice daily; prolonged-release is taken once daily in the morning. Do not swap between formulations without a monitoring plan; keep the same brand or manufacturer where possible.

Starting doses (oral).

• Kidney transplant: 0.1 mg/kg daily in 2 divided doses (prolonged-release 0.15 to 0.2 mg/kg once daily).
• Liver transplant: 0.1 to 0.15 mg/kg daily in 2 divided doses.
• Heart transplant: 0.075 mg/kg daily in 2 divided doses.
• Lupus nephritis and other non-transplant use: 0.05 to 0.1 mg/kg daily in 2 divided doses, with levels.
• Intravenous: 0.01 to 0.05 mg/kg daily as a continuous infusion, when oral therapy is not possible.

Target trough ranges (indicative; units differ).

• Kidney transplant: 8 to 12 ng/mL in the first 3 months, then 5 to 8 ng/mL.
• Liver transplant: 6 to 10 ng/mL early, then 4 to 8 ng/mL.
• Heart transplant: 10 to 15 ng/mL in the first 3 months, then 8 to 12 ng/mL.
• Lupus nephritis and nephrotic syndrome: 4 to 7 ng/mL.

Titration. Adjust by 10 to 25% of the dose for each level outside target, repeat the level in 3 to 5 days, and combine with clinical review.

Interactions (the main cause of unstable levels).

• Raise levels (reduce tacrolimus): azole antifungals, clarithromycin and erythromycin, diltiazem, verapamil, ritonavir and cobicistat, ciclosporin, grapefruit, amiodarone, metoclopramide.
• Lower levels (increase tacrolimus): rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, St John’s wort, high-dose corticosteroids.
• Nephrotoxic drugs (NSAIDs, aminoglycosides, amphotericin B, contrast) add kidney injury.

CYP3A5 genotype. Carriers of the CYP3A5*1 allele metabolise tacrolimus rapidly and need higher doses; this allele is more frequent in people of African ancestry, so some patients need 1.5 to 2 times the usual starting dose adjusted by early levels.

Kidney impairment. Dose is not adjusted for clearance, but levels and creatinine are followed closely; avoid nephrotoxins.

Liver impairment. Reduce the dose and monitor levels, since clearance falls.

Diarrhoea and gastrointestinal illness. May raise levels; check a trough and creatinine.

Pregnancy. Compatible; dose requirement often rises in the second and third trimesters and falls after birth; check levels every 4 weeks. Breastfeeding is acceptable with infant monitoring.

Adverse effects. Nephrotoxicity, hypertension, hyperkalaemia, hypomagnesaemia, new-onset diabetes, tremor, headache, neurotoxicity and rarely thrombotic microangiopathy.

Monitoring. Trough level twice weekly in the first 2 weeks after transplant, then weekly to 3 months, then monthly, and after any interacting drug, illness or dose change. Creatinine and potassium with every level; magnesium, glucose and blood pressure at each clinic visit.

Toxicity. Levels over 15 ng/mL (or over the target ceiling) with tremor, confusion, seizures, rising creatinine or hyperkalaemia: omit one or more doses, repeat the level, and restart at a reduced dose.

Acute kidney injury. Reduce the dose by 25 to 50% while the cause is sought; do not stop abruptly in transplant recipients without specialist advice.

Escalation. Refer to the transplant or rheumatology team for rejection, thrombotic microangiopathy, severe neurotoxicity, or persistently unstable levels.