What is cyclosporin?

What is Cyclosporin?

Cyclosporin (also spelled cyclosporine or ciclosporin) is a potent, noncytotoxic immunosuppressive drug that is a cyclic polypeptide of 11 amino acids, originally isolated from the fungus Tolypocladium inflatum, which works primarily by inhibiting T-cell activation and interleukin-2 production. 1, 2

Chemical Structure and Origin

• Cyclosporin is a neutral, hydrophobic cyclic polypeptide with a molecular weight of 1203 Da, consisting of 11 amino acids 1
• It was first isolated from the soil fungus Tolypocladium inflatum in 1970 1
• The drug is produced as a metabolite by this fungus species 2

Mechanism of Action

Cyclosporin works by binding to cytoplasmic cyclophillin (a cis-trans isomerase), and this complex then inhibits calcineurin phosphatase, which is essential for T-cell activation. 1, 3

The specific immunosuppressive pathway involves:

• Calcineurin normally dephosphorylates the nuclear factor of activated T cells (NFAT) 1, 3
• When cyclosporin inhibits calcineurin, NFAT cannot enter the nucleus 3
• This prevents transcription of lymphokines, most importantly interleukin-2 (IL-2), which is the major T-cell activation factor 1, 3
• The drug also inhibits production of other cytokines including interferon-gamma, granulocyte-macrophage colony-stimulating factor, IL-3, IL-4, and tumor necrosis factor-alpha 1

Primary Immunologic Effects

• The T-helper cell is the main target of cyclosporin's action 1, 2
• It suppresses both T-helper 1 (Th1) and T-helper 2 (Th2) cell responses 1
• The drug preferentially inhibits T-lymphocytes in the G0 or G1 phase of the cell cycle 2
• It reduces B-cell activation and antibody production secondarily through IL-2 inhibition 3
• Critically, cyclosporin does not cause bone marrow suppression, which distinguishes it from other immunosuppressants 2

Clinical Applications

Transplantation (Primary Use)

• Originally developed and FDA-approved for preventing organ transplant rejection in kidney, liver, heart, pancreas, bone marrow, and lung transplants 2, 4

Dermatologic Conditions

• Licensed for psoriasis and atopic dermatitis in patients ≥16 years old 5
• Effective for severe psoriasis vulgaris, erythrodermic psoriasis, generalized pustular psoriasis, and psoriatic nail dystrophy 5
• Used for severe atopic dermatitis refractory to conventional topical treatments 1, 5

Hematologic Disorders

• Used in immune thrombocytopenia (ITP) with response rates of 37.8% to 56.7% at 1 month 1
• Durable response rates in ITP range from 23.3% to 44% 1

Other Autoimmune Conditions

• Effective in acute ocular Behçet's syndrome, endogenous uveitis, rheumatoid arthritis, active Crohn's disease, and nephrotic syndrome 6
• May benefit patients with primary biliary cirrhosis, pyoderma gangrenosum, and polymyositis/dermatomyositis 6

Dosing

• Standard dosing range is 2.5-5 mg/kg/day orally, divided into two doses 5
• For severe disease requiring rapid control, start at 5 mg/kg/day 5
• For less urgent cases, start at 2.5-3 mg/kg/day and increase if needed 5
• In ITP, the usual starting dose is 3-6 mg/kg per day with a maximum of 200 mg for both adults and children 1
• Dose adjustments are made based on trough drug levels 1

Pharmacokinetics

• Oral absorption is slow, incomplete, and variable, with bioavailability ranging from less than 5% to 89% 7
• Peak blood concentrations occur approximately 3.5 hours after oral administration 2
• The microemulsion formulation has more consistent pharmacokinetics and approximately 10% higher bioavailability than the original formulation 1, 5
• The drug is widely distributed outside the blood volume with a volume of distribution of 0.9 to 4.8 L/kg 7
• In blood, approximately 33-47% is in plasma, with the remainder in lymphocytes, granulocytes, and erythrocytes 2
• Approximately 90% is bound to plasma proteins, primarily lipoproteins 2
• Terminal half-life is approximately 19 hours (range 10-27 hours) 2
• Elimination is primarily biliary with only 6% excreted in urine 2
• The drug is extensively metabolized by cytochrome P450 (especially CYP3A4), with only 0.1% excreted unchanged in urine 2

Major Adverse Effects

The most important hazards are nephrotoxicity and hypertension, which require careful monitoring. 1

Common adverse effects include:

• Gingival hyperplasia (6.6%) 1
• Hypertension (11.6%) 1
• Nephrotoxicity (6.7%) 1
• Nausea 1
• Hypertrichosis 6
• Neurological and gastrointestinal effects 6

Critical Monitoring Requirements

Before starting treatment:

• Complete physical examination, blood pressure, baseline serum creatinine, BUN, CBC, serum magnesium, potassium, uric acid, lipids, hepatitis screening, and pregnancy test 5

During treatment:

• Monitor serum creatinine and blood pressure every 2 weeks for the first 2 months 5
• Continue regular monitoring throughout treatment 5

Important Drug Interactions

• Cyclosporin is metabolized by CYP3A4, leading to numerous drug interactions 5
• Avoid aminoglycosides, amphotericin, trimethoprim, ketoconazole, phenytoin, rifampicin, isoniazid, and NSAIDs 5
• Use calcium channel blockers (especially isradipine) to manage cyclosporin-induced hypertension 5
• Avoid thiazide and potassium-sparing diuretics 5

Safety Considerations

• Cyclosporin has a relatively narrow therapeutic index, requiring careful balance between benefit and toxicity 1
• It is generally reserved for severe disease and considered a second-line agent, especially when treatment exceeds 2-3 months 1
• The drug is contraindicated in pregnancy and lactation for most indications 1
• Short-term intermittent courses (up to 6 months) are the safest approach to minimize long-term risks 5
• The drug should not be stopped abruptly in conditions like pustular psoriasis, as this can precipitate rebound flares 5