calcineurininhibitor

Calcineurin inhibitors are a class of immunosuppressive drugs that directly inhibit calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase essential for activating T-lymphocytes. By blocking calcineurin, these agents prevent dephosphorylation and nuclear translocation of the transcription factor NFAT, leading to reduced transcription of interleukin-2 and impaired T-cell proliferation.

The principal members of this class include cyclosporine and tacrolimus. Cyclosporine binds to cyclophilin, while tacrolimus binds to FKBP12; both drug–immunophilin complexes inhibit calcineurin. There are topical calcineurin inhibitors as well, such as pimecrolimus and tacrolimus, used mainly for inflammatory skin conditions. Voclosporin is a newer cyclosporine analogue with a similar mechanism. In addition to their systemic use in transplantation, CNIs are employed for certain autoimmune diseases and, in topical or ophthalmic formulations, for dermatologic and ocular conditions.

Clinical use centers on preventing organ transplant rejection and treating selected autoimmune diseases. Topical CNIs are used for atopic dermatitis and other inflammatory skin disorders, while ocular formulations of cyclosporine are used for dry eye.

Pharmacokinetics and monitoring are characterized by substantial interindividual variability and a narrow therapeutic index. CNIs are mainly hepatically metabolized by CYP3A4 and are prone to drug interactions. Therapeutic drug monitoring of trough levels is common to balance efficacy and toxicity.

Adverse effects include nephrotoxicity, hypertension, neurotoxicity, tremor, hyperkalemia, and hyperglycemia. There is an increased risk of infections and certain malignancies; cosmetic effects such as hirsutism and gum hypertrophy can occur with cyclosporine. Topical forms generally have fewer systemic effects.