Calcineurin inhibitors

1. Introduction

• Calcineurin inhibitors are a class of immunosuppressive agents that act by blocking the activity of calcineurin, a calcium/calmodulin-dependent serine–threonine phosphatase.

• Inhibit T-cell activation by preventing transcription of interleukin-2 (IL-2) and other cytokines.

• Widely used in organ transplantation to prevent rejection and in certain autoimmune disorders.

• Main agents: Cyclosporine and Tacrolimus (systemic use), and topical forms such as pimecrolimus and tacrolimus ointment for dermatological conditions.

---

2. Mechanism of Action

• Normal pathway: Antigen recognition → increased intracellular calcium → activation of calmodulin → activation of calcineurin → dephosphorylation of NFAT (nuclear factor of activated T cells) → transcription of IL-2 and other pro-inflammatory cytokines → T-cell proliferation.

• With CNIs:

  • Cyclosporine: binds to cyclophilin → complex inhibits calcineurin.

  • Tacrolimus: binds to FK-binding protein-12 (FKBP-12) → complex inhibits calcineurin.

  • Result: NFAT remains phosphorylated → no IL-2 transcription → suppressed T-cell activation.

---

3. Pharmacological Agents

A. Systemic CNIs

• Cyclosporine (Sandimmune, Neoral, Gengraf)

• Tacrolimus (Prograf, Advagraf, Envarsus XR)

B. Topical CNIs

• Tacrolimus ointment (Protopic) – atopic dermatitis, other inflammatory dermatoses.

• Pimecrolimus cream (Elidel) – mild to moderate atopic dermatitis.

---

4. Pharmacokinetics

Cyclosporine

• Absorption: variable oral bioavailability (20–50%); enhanced by microemulsion formulations.

• Metabolism: hepatic via CYP3A4.

• Elimination half-life: ~6–27 hours.

Tacrolimus

• Absorption: oral bioavailability ~20–25%; affected by food.

• Metabolism: hepatic via CYP3A4 and CYP3A5.

• Elimination half-life: ~8–12 hours (longer in hepatic impairment).

---

5. Therapeutic Indications

A. Organ Transplantation

• Prevention of acute and chronic rejection in kidney, liver, heart, and lung transplantation (often in combination with corticosteroids and antiproliferative agents).

B. Autoimmune Diseases

• Severe psoriasis (cyclosporine).

• Severe rheumatoid arthritis (cyclosporine).

• Myasthenia gravis (cyclosporine).

• Certain uveitis cases.

C. Dermatology (Topical CNIs)

• Atopic dermatitis (steroid-sparing).

• Vitiligo (off-label).

• Chronic hand eczema (off-label).

• Lichen planus (off-label topical).

---

6. Contraindications

• Hypersensitivity to the active drug or formulation components.

• Uncontrolled hypertension (cyclosporine systemic use).

• Uncontrolled infections.

• Malignancy (relative contraindication; weigh risks/benefits).

---

7. Adverse Effects

Systemic

• Nephrotoxicity (dose-dependent; major limiting factor).

• Hypertension.

• Hyperlipidemia (more with cyclosporine).

• Neurotoxicity (tremor, headache, seizures).

• Hyperglycemia and new-onset diabetes (more with tacrolimus).

• Hyperkalemia, hypomagnesemia.

• Increased infection risk.

• Gingival hyperplasia (cyclosporine).

• Hirsutism (cyclosporine).

• Alopecia (tacrolimus).

Topical

• Burning, stinging, pruritus at application site (usually transient).

• Increased local infection risk (rare).

• Theoretical long-term cancer risk – led to “black box” warning, though evidence is limited.

---

8. Drug Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, grapefruit juice) → ↑ CNI levels → toxicity risk.

• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) → ↓ CNI levels → rejection risk.

• Additive nephrotoxicity with aminoglycosides, amphotericin B, NSAIDs.

• Potassium-sparing diuretics (e.g., spironolactone) → ↑ hyperkalemia risk.

---

9. Monitoring Requirements

• Trough drug levels (especially early post-transplant) to ensure efficacy and minimize toxicity.

• Renal function (serum creatinine, BUN).

• Blood pressure.

• Blood glucose (for tacrolimus).

• Lipid profile (for cyclosporine).

• Electrolytes (potassium, magnesium).

---

10. Special Precautions

• Avoid live vaccines during therapy.

• Adjust doses in hepatic impairment.

• Minimize exposure to sunlight/UV light (slightly increased malignancy risk).

• Careful dosing in elderly due to reduced renal clearance.

---

11. Advantages and Limitations

Advantages

• Highly effective in preventing acute transplant rejection.

• Selective suppression of T-cell activation without broad myelosuppression.

• Topical forms avoid systemic immunosuppression and steroid-related skin atrophy.

Limitations

• Narrow therapeutic index – requires drug level monitoring.

• Chronic nephrotoxicity limits long-term use.

• Significant drug–drug interaction potential.

• Long-term risk of malignancies with systemic immunosuppression.