Calcineurin inhibitors and immunophilias

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Ciclosporin Sandimmun, Neoral

Pharmacological Group: Immunosuppressant, calcineurin inhibitor.

Mechanism of Action: It binds intracellularly to cyclophilin, forming a complex that blocks the phosphatase activity of calcineurin. Under normal conditions, calcineurin dephosphorylates nuclear factor of activated T cells (NFAT) in response to TCR-mediated calcium influx. Inhibition of this process prevents the nuclear translocation of NFAT, suppressing the transcription of the interleukin-2 (IL-2) gene and the clonal proliferation of helper and cytotoxic T lymphocytes.

Monitoring and Critical Adjustments

Due to its narrow therapeutic range, monitoring of plasma levels in whole blood is mandatory. The standard trough level (C₀) ranges between 100-400 ng/mL depending on the type of transplant and the time elapsed since surgery. Alternatively, monitoring at 2 hours post-dose (C₂) provides superior correlation with area under the curve (AUC). In case of severe liver failure, it is necessary to reduce the initial dose by 50% and guide treatment strictly by trough levels.

Contraindications and Risk Interactions

Absolute contraindications: Hypersensitivity to the active ingredient or excipients (such as polyoxyethylated castor oil in the IV formulation, associated with anaphylaxis); pre-existing renal dysfunction unrelated to the immunological indication; uncontrolled arterial hypertension; active uncontrolled infections.
High Risk Clinical Interactions:

• Increased toxicity due to CYP3A4 inhibition: Concomitant use of ketoconazole, erythromycin, diltiazem or grapefruit juice drastically increases cyclosporine levels, increasing the risk of acute nephrotoxicity.
• Loss of efficacy due to CYP3A4 induction: Rifampicin, phenytoin and St. John's wort accelerate its clearance, inducing acute graft rejection.
• Synergistic nephrotoxicity: Avoid association with NSAIDs, aminoglycosides and amphotericin B.

Pregnancy: Category C (crosses placenta, risk of IUGR) Breastfeeding: Contraindicated Tacrolimus Prograf, Advagraf, Envarsus

Pharmacological Group: Immunosuppressant, calcineurin inhibitor.

Mechanism of Action: Unlike cyclosporine, tacrolimus binds intracellularly to the immunophilin FKBP-12. This resulting complex inhibits calcineurin in an identical manner, preventing the translocation of NFAT and, consequently, silencing the transcription of IL-2 and other cytokines (IL-3, IL-4, IFN-gamma). It has an in vitro immunosuppressive potency between 10 and 100 times greater than cyclosporine.

Clinical Pearl: CYP3A5 genotype and dosage

Interindividual variability in tacrolimus dose requirements is strongly determined by the genetic polymorphism of CYP3A5. Patients classified as "rapid expressers" (carriers of the wild-type alleles *1/*1 or *1/*3) clear the drug with extraordinary rapidity and require significantly higher doses to reach target levels compared to "non-expressors" (carriers of the low-activity alleles *3/*3), prevalent in the Caucasian population.

Risk and Dosage Interactions

Guideline Dosage: Renal transplant: 0.1-0.2 mg/kg/day PO divided into two doses (immediate release) or a single morning dose (Advagraf). Adjust according to trough levels (target: 5-15 ng/mL in whole blood).
Liver Failure: Reduce initial dose by half and monitor daily.
Most Relevant Interactions:

• Enzyme inhibitors (voriconazole, posaconazole, clarithromycin) can trigger trough levels, causing severe acute nephrotoxicity. The use of voriconazole typically requires an immediate 33% to 50% reduction in the tacrolimus dose.
• Prolongation of the QTc interval: Avoid concomitant administration with other drugs that prolong the QT interval (macrolides, quinolones, ondansetron, amiodarone) due to the risk of Torsades de Pointes.

Pregnancy: Category C (associated with transient neonatal hyperkalemia) Breastfeeding: Not recommended