Cyclosporin (Cyclosporin A)

Mechanism

Pharmacological Class and Group

Systemic immunosuppressant of the class of Calcineurin Inhibitors (lipophilic cyclic peptide of fungal origin extracted from the fungus Tolypocladium inflatum).

Mechanism of Action

Cyclosporine acts on T helper lymphocytes (CD4+) by blocking the transcription of essential immunoregulatory interleukins.

Immunosuppressive Cellular Action Mechanism

1. Binding to Cyclophilin: Cyclosporine diffuses through the T lymphocyte membrane and selectively binds to a specific intracellular cytosolic immunophilin: cyclophilin (Cyp-18).

2. Inactivation of Calcineurin: The Cyclosporin-Cyclofilin complex couples to the heterodimeric phosphatase calcineurin, inhibiting its intrinsic dephosphorylating enzymatic activity.

3. Stop of the Genomic Activation of Lymphocytes: Since the cytoplasmic component of the transcription factor NFAT-c is not dephosphorylated, it is unable to translocate to the nucleus:

Cyclosporin Inhibition of Calcineurin No translocation of NFAT Stopping Th1 / Th17 Clones

As a result, the transcription of IL-2 (T cell growth factor) is almost instantly suppressed, blocking cellular progression from the G0 to G1 phase of the lymphocyte cell cycle and the systemic synthesis of IFN-γ, IL-17 and TNF-α.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption: Variable and incomplete oral absorption. Microemulsified formulations (Neoral) substantially improve the consistency of absorption and decrease dependence on gastric emptying and bile salts.
• Distribution: Widely distributed in lipophilic body tissues. It binds extensively to plasma lipoproteins in more than 90%.
• Metabolism: Extremely extensive phase I hepatic metabolism mediated exclusively by the cytochrome P450 isoenzyme CYP3A4, generating inactive bile clearance metabolites.
• Excretion: Almost exclusive elimination through the bile and fecal route (90-95%); Less than 5% of the administered dose is eliminated by unchanged renal filtration.
• Half-life (t_1/2): Terminal elimination half-life of approximately 8 to 18 hours depending on age and individual metabolic clearance.

Indicators and dose

Clinical Indications and Off-Label Uses

• Severe Refractory Plaque Psoriasis: Especially indicated as temporary rapid induction therapy ("bridge therapy") due to its speed of action (2-4 weeks).
• Severe Atopic Dermatitis that is Difficult to Control: Rapid suppression of pruritus and erythema in adults and pediatrics.
• Pyoderma Gangrenosum (off-label): Immune control of severe destructive neutrophilic ulcers.
• Autoimmune Bullous Dermatoses (off-label): Pemphigus vulgaris or bullous pemphigoid refractory to basic corticosteroids.

Dosage and Clinical Adjustment

• Rapid Induction Dose: 3 to 5 mg/kg/day orally, strictly divided into two daily doses separated by 12 hours (e.g., at 8:00 AM and 8:00 PM) to stabilize plasma levels.
• Usual Maintenance Dose (Medium-term Management): Once the inflammatory outbreak is controlled, it is gradually lowered in steps of 0.5-1.0 mg/kg/day to the minimum tolerated effective dose (usually between 1.5 and 3 mg/kg/day).
• It is not advisable to maintain treatment for continuous periods of more than 1 year, except in situations of extreme therapeutic rebellion where the patient is monitored with ultrasound or measured creatinine clearance.

Adjustment in Renal Failure: Contraindicated if baseline creatinine clearance is < 50-60 mL/min, or if creatinine persistently rises above 30% of the basal level after titration.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to cyclosporine or components (such as polyoxyethylated castor oil in the infusion).
• Uncontrolled systemic arterial hypertension of any origin.
• Significant pre-existing renal dysfunction (elevated baseline creatinine or eGFR < 50 mL/min).
• Uncontrolled systemic bacterial, fungal or viral infections.
• Active presence of cutaneous (except superficial BCC) or systemic malignant neoplasms.

Relative Contraindications

• Concomitant use with live attenuated vaccines.
• Severe baseline hyperkalemia or hyperuricemia.
• Concomitant treatments with strong inducers or inhibitors of the CYP3A4 enzyme.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>15%): Acute nephrotoxicity (reversible functional renal failure), Systemic arterial hypertension, fine hand tremor, distal or oral paresthesias.
• Frequent (1%-10%): Inflammatory gingival hyperplasia (often facilitated by poor oral hygiene), de novo hypertrichosis of the face and trunk, mixed hyperlipidemia, hyperuricemia (which can trigger outbreaks of acute joint gout), hyperkalemia due to suppression of the aldosterone axis.
• Uncommon (0.1%-1%): Refractory anemia, mild leukopenia, fatigue, headache.

Critical Toxicity: Chronic Nephrotoxicity and Hypertension due to Cyclosporine

Nephrotoxicity is the most serious limiting adverse effect of cyclosporine and is divided into two distinct phases:

1. Acute Nephrotoxicity (Functional and Reversible): It is due to the induction of a powerful and reversible vasoconstriction of the glomerular afferent arteriole, mediated by an increase in endothelin tone and thromboxane A2. It causes an immediate decrease in the glomerular filtration rate (GFR) with an increase in serum creatinine.

2. Chronic Nephrotoxicity (Irreversible): If treatment is prolonged uninterruptedly for more than 1 to 2 years, sustained chronic renal ischemia induces sclerosis of the afferent arteriole, with patchy renal interstitial fibrosis ("stripe-like fibrosis") and irreversible tubular atrophy. Continuous use of cyclosporine in dermatology should be limited to maximum periods of 12 months, monitoring blood pressure and determining serum creatinine biweekly at the beginning and monthly thereafter. If creatinine increases more than 30% compared to the patient's baseline value, the dose should be reduced immediately by 25-50%, and discontinued if not corrected within 30 days.

Drug Interactions of Clinical Relevance

• Potent CYP3A4 inhibitors (Clarithromycin, Ketoconazole, Itraconazole, Amiodarone, Ritonavir, Grapefruit Juice): They exponentially increase the bioavailability and plasma levels of cyclosporine, precipitating acute nephrotoxicity and severe hypertension. Requires drastic dose reduction or avoidance.
• CYP3A4 inducers (Rifampin, Carbamazepine, Phenytoin, St. John's Wort): They drastically accelerate the clearance of the drug, completely reducing its immunosuppressive efficacy.
• Nephrotoxic Drugs (NSAIDs, Aminoglycosides, Vancomycin): Toxic synergism that directly damages the renal tubules quickly.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Compatible with specific precautions. It does not have the intrinsic teratogenic potential of methotrexate. Data in transplanted women exposed to cyclosporine show a modest increase in the risk of preterm birth and intrauterine growth retardation secondary to maternal systemic vasoconstriction. Its indication is reserved in pregnant women for extreme uncontrollable dermatological outbreaks (e.g., pustular psoriasis of pregnant women or impetigo herpetiformis).
• Breastfeeding: Contraindicated. Being a lipophilic cyclic peptide highly concentrated in lipids, it is excreted in significant quantities in human milk, inducing potential immunosuppression and nephrotoxicity in the infant.