Introduction
Cyclosporine is a potent immunosuppressive agent that revolutionized organ transplantation when it was introduced in the 1980s. This calcineurin inhibitor is a cyclic polypeptide consisting of 11 amino acids, originally isolated from the fungus Tolypocladium inflatum. It remains a cornerstone therapy in preventing organ rejection and treating various autoimmune conditions.
Mechanism of Action
Cyclosporine exerts its immunosuppressive effects primarily by inhibiting calcineurin, a calcium-dependent phosphatase. This inhibition prevents the dephosphorylation and nuclear translocation of nuclear factor of activated T-cells (NFAT), a critical transcription factor for T-lymphocyte activation. By blocking this pathway, cyclosporine inhibits interleukin-2 (IL-2) production and subsequent T-cell proliferation, thereby suppressing the cell-mediated immune response.
Indications
FDA-approved indications:- Prevention of organ rejection in kidney, liver, and heart transplantation
- Severe, active rheumatoid arthritis (in patients who have failed methotrexate)
- Severe psoriasis in adults (when other therapies have failed)
- Treatment of nephrotic syndrome in patients with minimal change nephropathy
- Prevention of rejection in other solid organ transplants
- Autoimmune diseases including atopic dermatitis, ulcerative colitis, and Crohn's disease
- Aplastic anemia
- Beheet's disease
Dosage and Administration
Transplantation:- Initial dose: 12-15 mg/kg/day orally, divided into two doses, starting 4-12 hours before transplantation
- Maintenance: 2-10 mg/kg/day, adjusted based on trough concentrations
- IV administration: ⅓ of oral dose (3-5 mg/kg/day) as continuous infusion
- Rheumatoid arthritis: 2.5-4 mg/kg/day in divided doses
- Psoriasis: 2.5-4 mg/kg/day in divided doses, maximum 4 mg/kg/day
- Renal impairment: Dose reduction required
- Hepatic impairment: Significant dose reduction necessary
- Elderly: Lower doses may be required due to decreased renal function
- Pediatrics: Dosing based on body surface area or weight
Pharmacokinetics
Absorption: Variable and incomplete (20-50% bioavailability); enhanced by fatty meals Distribution: Extensive tissue binding; volume of distribution: 3-5 L/kg; highly protein bound (90%) Metabolism: Extensive hepatic metabolism via CYP3A4 enzyme system Elimination: Primarily biliary excretion; elimination half-life: 19-27 hours Note: Significant interpatient variability necessitates therapeutic drug monitoringContraindications
- Hypersensitivity to cyclosporine or any component of the formulation
- Uncontrolled hypertension
- Malignancies (relative contraindication)
- Concurrent use with potent CYP3A4 inhibitors where alternative therapy is unavailable
- Live vaccinations during therapy
Warnings and Precautions
Black Box Warnings:- Increased susceptibility to infection and development of lymphoma
- Nephrotoxicity (both acute and chronic)
- Hypertension
- Hepatotoxicity
- Neurotoxicity (tremor, seizures, encephalopathy)
- Hyperkalemia
- Hyperuricemia and gout
- Hirsutism and gingival hyperplasia
- Increased risk of skin malignancies
- Pure red cell aplasia has been reported
Drug Interactions
Major interactions:- CYP3A4 inhibitors: Ketoconazole, fluconazole, erythromycin, clarithromycin, verapamil, diltiazem (increase cyclosporine levels)
- CYP3A4 inducers: Rifampin, phenytoin, phenobarbital, St. John's wort (decrease cyclosporine levels)
- Nephrotoxic agents: Aminoglycosides, amphotericin B, NSAIDs (increased renal toxicity risk)
- Potassium-sparing diuretics: Increased hyperkalemia risk
- Statins: Increased risk of myopathy and rhabdomyolysis
Adverse Effects
Common (≥10%):- Hypertension
- Nephrotoxicity
- Tremor
- Hirsutism
- Hypertrichosis
- Headache
- Gastrointestinal disturbances
- Gingival hyperplasia
- Hyperlipidemia
- Progressive renal dysfunction
- Hepatotoxicity
- Neurotoxicity (seizures, encephalopathy)
- Anaphylaxis (with IV administration)
- Thrombotic microangiopathy
- Opportunistic infections
- Malignancies (particularly skin cancer and lymphoma)
Monitoring Parameters
Essential monitoring:- Cyclosporine trough levels (target range varies by indication: 100-400 ng/mL)
- Serum creatinine (at least twice weekly initially)
- Blood pressure
- Liver function tests
- Complete blood count
- Electrolytes (especially potassium and magnesium)
- Lipid profile
- Urinalysis for proteinuria
- Therapeutic drug monitoring for efficacy and toxicity
- Signs of infection
- Neurological assessment
Patient Education
Key points for patients:- Take medication at the same times each day, consistently with regard to meals
- Do not discontinue abruptly without medical supervision
- Avoid grapefruit and grapefruit juice during therapy
- Use effective contraception (cyclosporine is pregnancy category C)
- Practice sun protection due to increased skin cancer risk
- Report any signs of infection, unusual bruising/bleeding, or neurological symptoms
- Maintain regular dental care due to risk of gingival hyperplasia
- Inform all healthcare providers about cyclosporine therapy
- Keep all scheduled laboratory appointments for therapeutic monitoring
- Avoid live vaccines during treatment
References
1. Kahan BD. Cyclosporine. N Engl J Med. 1989;321(25):1725-1738. 2. The U.S. Cyclosporine Kidney Transplant Study Group. Cyclosporine in renal transplantation: a five-year follow-up. Transplantation. 1990;49(1):19-25. 3. FDA Prescribing Information: Sandimmune (cyclosporine). Revised 2021. 4. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326-2333. 5. Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N Engl J Med. 1992;326(25):1654-1660. 6. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995;17(6):584-591. 7. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98(1):19-24.