Cyclosporine

Cyclosporine, also known as cyclosporin A, is an immunosuppressive cyclic peptide derived from the fungus Tolypocladium inflatum. It is used primarily to prevent graft rejection in solid-organ transplantation and to treat certain autoimmune diseases. A ophthalmic preparation is also available for the treatment of dry eye disease.

Mechanism of action

Cyclosporine binds to the intracellular protein cyclophilin to form a complex that inhibits calcineurin. This prevents dephosphorylation of NFAT and the transcription of interleukin-2 and other cytokines, thereby suppressing T-cell activation and proliferation. The immunosuppressive effect is mainly on T lymphocytes, reducing cellular immune responses.

Medical uses

In transplantation, cyclosporine is used for prophylaxis of acute rejection in kidney, liver, and heart transplants, often as part of a multi-drug regimen. It is also used to prevent graft-versus-host disease in allogeneic stem cell transplantation. Autoimmune indications include rheumatoid arthritis, psoriasis, Crohn’s disease, and ulcerative colitis in some cases. The ophthalmic form (topical) is approved for dry eye disease to reduce inflammation and improve tear production.

Pharmacokinetics and formulation

Cyclosporine is available orally and intravenously, with substantial interpatient variability in bioavailability. It is extensively metabolized by hepatic CYP3A4 and P-glycoprotein, and elimination occurs mainly via the bile. Drug levels and dosing are adjusted through therapeutic drug monitoring. The formulation and route influence absorption and exposure.

Adverse effects and monitoring

Key risks include nephrotoxicity, hypertension, hyperkalemia, hyperlipidemia, tremor, hirsutism, gingival hyperplasia, and neurotoxicity. There is an increased susceptibility to infections and a potential risk of lymphoproliferative disorders. Hepatotoxicity can occur. Patients require regular monitoring of renal and liver function, blood pressure, electrolytes, and trough drug levels. Cyclosporine has important drug interactions, particularly with potent CYP3A4 inhibitors and inducers, which can raise or lower blood levels and toxicity risk. Pregnancy considerations require careful benefit–risk assessment.