Ciclosporin (also spelled cyclosporine) is a potent immunosuppressant and calcineurin inhibitor, primarily used to prevent rejection of transplanted organs such as the kidney, liver, heart, and bone marrow, as well as to treat certain autoimmune disorders. It was discovered in 1970 by Sandoz scientists from the fungus Tolypocladium inflatum and initially studied for its antifungal properties. In 1972, Jean Borel’s team identified its strong immunosuppressive effect, which selectively inhibits lymphocytes and significantly reduces organ rejection. Clinical trials in the late 1970s led to the first successful kidney transplant using cyclosporine in 1980, and it was FDA-approved in 1983, quickly becoming the standard drug for immunosuppression in transplantation.
BRAND NAMES
Ciclosporin (Cyclosporine) include Gengraf, Neoral, and Sandimmune. Additional brands such as Restasis, Cequa, and Ikervis are primarily used for treating specific eye conditions.
Neoral: Microemulsion form for improved absorption and consistent blood levels.
Sandimmune: Original formulation; absorption can be variable.
Gengraf: Alternative microemulsion form similar to Neoral.
Generic Cyclosporine: Available in capsule, oral solution, and injectable forms.
MECHANISM OF ACTION
Ciclosporin is an immunosuppressant that primarily inhibits T-lymphocyte activation. It binds to the cytoplasmic protein cyclophilin, forming a complex that inhibits calcineurin. This prevents transcription of interleukin-2 and other cytokines necessary for T-cell proliferation. By suppressing the immune response, it reduces the risk of organ transplant rejection and treats autoimmune disorders. Its effect is selective to T-cells, leaving other immune components relatively unaffected.
PHARMACOKINETICS:
Absorption
Ciclosporin is absorbed variably in the gastrointestinal tract, influenced by the formulation (microemulsion vs. standard).
Distribution
Widely distributed in tissues, highly protein-bound (~90%), and accumulates in the liver, kidney, and lymphoid tissue.
Metabolism
Extensively metabolized in the liver via CYP3A4 enzymes.
Excretion:
Mainly eliminated via bile; less than 10% is excreted unchanged in urine.
PHARMACODYNAMICS
Ciclosporin suppresses the immune system by selectively inhibiting T-cell activation and cytokine production. Its immunosuppressive effects reduce organ rejection in transplant patients and help manage autoimmune diseases like psoriasis or rheumatoid arthritis. The drug is dose-dependent, with therapeutic levels monitored to balance efficacy and toxicity. Its onset of action is gradual, requiring consistent dosing and monitoring. Long-term use can lead to cumulative toxicity if not properly managed.
ADMINISTRATION
Ciclosporin is administered orally (capsules or solution) or intravenously in hospital settings. Oral microemulsion forms are preferred for consistent absorption. Doses are individualized based on body weight, type of transplant, or autoimmune condition. Blood levels are regularly monitored to maintain therapeutic range. It should be taken consistently with or without food, following the specific formulation instructions.
DOSAGE AND STRENGTH
Typical oral doses range from 2–6 mg/kg/day for transplant patients, divided into two doses. Autoimmune conditions may require lower doses. Dose adjustments are made based on blood concentration monitoring. Microemulsion forms generally require lower doses than standard formulations. Pediatric and renal-impaired patients require careful dose titration.
DRUG INTERACTIONS
Ciclosporin interacts with many drugs that affect CYP3A4 and P-glycoprotein, including:
Ketoconazole, erythromycin (increase ciclosporin levels)
Rifampin, phenytoin (decrease ciclosporin levels)
NSAIDs and aminoglycosides (increase risk of nephrotoxicity)
Close monitoring is essential when co-administered with other medications.
FOOD INTERACTIONS
Absorption can be affected by high-fat meals, grapefruit juice (increases blood levels), and St. John’s Wort (reduces levels). It should generally be taken consistently with regard to meals. Avoiding sudden changes in diet helps maintain stable drug levels. Adequate hydration is recommended to reduce nephrotoxicity risk.
CONTRAINDICATIONS
Ciclosporin is contraindicated in patients with hypersensitivity to the drug. Severe uncontrolled hypertension or malignancies are relative contraindications. Active infections must be managed before therapy. Liver impairment may require dose adjustments or avoidance. Careful evaluation is needed before use in pregnancy or breastfeeding.
SIDE EFFECTS
Increased hair growth (hirsutism), especially on the face, arms, or back.
Gum overgrowth or tenderness (gingival hyperplasia).
Tremors or uncontrollable shaking.
Headache.
High blood pressure (hypertension).
Nausea, vomiting, diarrhea, or stomach pain.
Tingling or numbness in the hands or feet.
Fatigue or unusual tiredness.
Muscle or joint pain and cramps.
Acne.
OVER DOSE
Overdose can lead to severe nephrotoxicity, hypertension, and neurotoxicity. Symptoms may include dizziness, nausea, vomiting, and tremors. Treatment is mainly supportive, with careful monitoring of kidney function and drug levels. Hemodialysis is not effective due to high protein binding. Immediate medical attention is required in suspected overdose cases.
TOXICITY
Chronic toxicity primarily affects the kidneys, leading to interstitial fibrosis and reduced renal function. Other toxic effects include liver dysfunction, neurotoxicity, and increased susceptibility to infections. Blood levels should be regularly monitored to avoid cumulative toxicity. Early detection and dose adjustment help minimize long-term damage. Supportive care is essential in managing severe toxicity.
