Calcineurin Inhibitors: Current Role, Toxicity Management, and Future Frontiers in Immunosuppression

Cyclosporine, tacrolimus, pimecrolimus and newer derivatives of cyclosporine such as voclosporin are calcineurin inhibitors (CNIs), have a potent immunosuppressant effect. They act by inhibiting the calcium dependent phosphatase, calcineurin. This process inhibits the phosphorylation of Nuclear Factor of Activated T-cells (NFAT) and the transcription of IL-2, which results in impaired T-cell activation. CNIs are important agents of transplant immunosuppression and are called in many auto-immune diseases. Dual disease-modifying antirheumatic drugs (DMARDs) and new immunomodulatory agents (IIAs), including voclosporin for lupus nephritis and pimecrolimus for atopic dermatitis, have led to stimulate further treatment possibilities in middle- and high-income countries (HICs). Although the treatment via CNI is effective, they cause serious dose-related side effects; these are nephrotoxicity, hypertension, neurotoxicity and metabolic disturbances. This necessitates the need of continuous monitoring of drug concentrations and management of cardiovascular and metabolic risk factors. This narrative review summarizes the mechanism(s), the current clinical application(s), the safety concern(s), and the future direction(s) of the safer and targeted use of CNIs.