Calcineurin Inhibitors

Calcineurin inhibitors (CNIs) are the backbone of transplant immunosuppression and treat nephrotic syndrome, uveitis, severe psoriasis, atopic dermatitis and selected autoimmune diseases. Tacrolimus and ciclosporin have a narrow therapeutic range, need blood level monitoring and interact with many drugs. Nephrotoxicity limits long-term use.

Mechanism. Tacrolimus binds FKBP12 and ciclosporin binds cyclophilin; each complex inhibits calcineurin, which blocks NFAT-driven transcription of interleukin 2 and T cell activation.

Pharmacokinetics. Highly variable oral absorption; metabolised by CYP3A4 and transported by P-glycoprotein; half-life 8 to 12 hours (tacrolimus 12 hours; ciclosporin about 8 hours); extensively bound to red cells, so whole blood levels are measured.

Tacrolimus.

• Kidney and liver transplant: 0.1 to 0.2 mg/kg daily in two divided doses; extended-release once daily.
• Target trough 5 to 10 ng/mL for maintenance (higher early, 8 to 15 ng/mL).
• Topical 0.03% and 0.1% ointment for atopic dermatitis.
• Lupus nephritis (multitarget): 2 to 4 mg daily.

Ciclosporin.

• Transplant: 8 to 10 mg/kg daily in two doses, adjusted to trough 100 to 200 ng/mL (modified formulation).
• Rheumatoid arthritis: 2.5 to 5 mg/kg daily; psoriasis 2.5 to 5 mg/kg; nephrotic syndrome 3 to 5 mg/kg.
• Do not switch brands without monitoring; modified (microemulsion) and original forms differ in absorption.

Voclosporin. 23.7 mg twice daily with mycophenolate and glucocorticoid for lupus nephritis (renal function based monitoring).

Administration. Take at the same time each day, with consistent meal timing; avoid grapefruit juice.

• First-line. Transplant maintenance (tacrolimus preferred in kidney and liver); topical tacrolimus for atopic dermatitis on face.
• Alternative. Ciclosporin when tacrolimus is not tolerated (diabetes, neurotoxicity) or unavailable; steroid-resistant nephrotic syndrome.
• Specialist. Lupus nephritis, severe uveitis, aplastic anaemia, graft-versus-host disease, severe psoriasis.
• Emergency. Acute rejection (levels, pulse steroid, specialist care).

Selection. Choose tacrolimus for greater potency and less hirsutism and gum change; choose ciclosporin when diabetes risk, neurotoxicity or tremor is a concern.

Contraindications. Hypersensitivity; uncontrolled hypertension (ciclosporin); severe renal impairment (unless transplant); malignancy (for psoriasis use); concurrent PUVA or other immunosuppression.

Serious adverse effects.

• Nephrotoxicity (acute vasoconstriction and chronic fibrosis), hypertension, hyperkalaemia, hypomagnesaemia.
• Neurotoxicity: tremor, headache, seizures, posterior reversible encephalopathy.
• Post-transplant diabetes (tacrolimus), hyperlipidaemia, hirsutism and gum hyperplasia (ciclosporin).
• Infection, lymphoma and skin cancer.

Major interactions. Raised levels: azole antifungals, macrolides (not azithromycin), diltiazem, verapamil, grapefruit; lowered levels: rifampicin, phenytoin, carbamazepine, St John’s wort. Nephrotoxic additive: NSAIDs, aminoglycosides, amphotericin. Potassium-raising drugs.

Common prescribing errors.

• Starting or stopping an interacting drug (especially rifampicin or an azole) without adjusting the dose.
• Switching brands or generics without level checks.
• Missing hyperkalaemia and renal function checks.
• Prescribing NSAIDs.
• Treating a level as the only guide when graft function changes.

Special groups.

• Pregnancy: tacrolimus and ciclosporin compatible; monitor levels, which fall in pregnancy.
• Breastfeeding: low transfer; generally acceptable with monitoring.
• Children: higher weight-based doses and faster clearance.
• Older adults: lower doses; renal risk.
• Kidney: dose by level; avoid other nephrotoxins.
• Liver: reduce dose; levels higher.
• East Africa: rifampicin for tuberculosis lowers levels by more than half, so increased doses and close monitoring are needed; azole antifungals do the opposite; trough testing may need referral, and generic tacrolimus substitution needs supervision.

Monitoring. Trough levels (twice weekly early, then monthly to quarterly); creatinine, potassium, magnesium, glucose, lipids and blood pressure; neurological symptoms; skin examination.

Referral and escalation. Rising creatinine; toxic levels; seizures; rejection; drug interaction needing dose change; pregnancy.

Comparison with alternative classes. CNIs are more potent than antimetabolites alone and prevent acute rejection, but damage kidneys over time. mTOR inhibitors and belatacept are renal-sparing alternatives with their own limits.