Cyclosporine

Mechanism of Action

Cyclosporine works to suppress cell-mediated immune reactions. Research has detected no effects on phagocytic function in animals, and it does not cause bone marrow suppression in animal or human models.[6][7]

The mechanism of action of cyclosporine is as a calcineurin inhibitor, a cytochrome P450 3A4 inhibitor, and a P-glycoprotein inhibitor. Cyclosporin A (CsA) inhibits the synthesis of interleukins (IL), including IL-2, which is essential for the self-activation of T lymphocytes (LT) and their differentiation. Cyclosporine is effective due to specific and reversible inhibition of immunocompetent lymphocytes in the G0 and G1-phase of the cell cycle. The T-helper cell is the primary target, although it may also suppress T-suppressor cells. The LT-B-lymphocyte (LB) co-operation is essential for activation of LB; the latter also gets inhibited. In addition, research has demonstrated that CsA had an inhibiting effect on CD4+ CD25+ Tregs, which might block the host immune tolerance potentiality.

Metabolism: Via hepatic CYP3A4 and is metabolized into a pair of hydroxylated derivatives (AM1 and AM9) and one N-methylated derivative (AM4N).

Enzymes inhibited: CYP3A4 and P-glycoprotein.

Half-Life: 8.4 to 27 hours: The time to peak blood cyclosporine concentrations (Tmax) ranges from 1.5 to 2 hours following oral administration of cyclosporine oral solution USP modified.

Clearance: 5 to 7 mL/min/kg in patients who are recipients of renal or liver allografts while appearing to be somewhat slower in cardiac transplant patients.

Excretion: Mainly bile and feces.

Factors known to influence absorption: Time post-transplant, bile flow, dietary composition, gastrointestinal state, liver function, small bowel length, and vehicle.

Administration

Dosing for Organ Transplant in Adults

Oral

• Four to 12 hours pre-transplant: 14 to 18 mg/kg by mouth for one dose.
• One to two weeks post-transplant: 5 to 15 mg/kg per day by mouth divided twice a day.
• Reduce the dose by 5% per week until 5 to 10 mg/kg per day by mouth divided twice per day.

Intravenous (IV) (maximum concentration 2.5 mg/dL)

• Four to 12 hours pre-transplant IV: 5 to 6 mg/kg IV for one dose over 2 to 6 hours.
• Post-transplant until the patient can tolerate oral therapy: 2 to 10 mg/kg IV once per day.
• Adjust dosage according to trough levels.

Focal segmental glomerulosclerosis: Oral 3 mg/kg/day every 12 hours.

Rheumatoid arthritis: Oral (modified), initially: 2.5 mg/kg per day every 12 hrs, increase 0.5 to 0.75 mg/kg per day after eight weeks if the response has not been effective. Maximum dose: 4 mg/kg per day.

Psoriasis: Oral (modified), initially: 2.5 mg/kg per day every 12 hours, increase 0.5 mg/kg per day after four weeks if the response has not been effective. Maximum dose: 4 mg/kg per day.

Adverse Effects

Cardiovascular: Hypertension, arrhythmia.

Renal: Decreases glomerular filtration rate (GFR) due to an increased tone of the glomerular afferent arterioles. Serum creatinine concentration rises and decreases creatinine clearance. The undesirable effects correlate with the duration of treatment and dose.

Endocrinological and metabolic: Dyslipidemia (predisposing factors such as hypertension), hypomagnesemia, hyperkalemia, gynecomastia, hypertrichosis.

Neurotoxicity: There have been reports of convulsions, especially in combination with high dose methylprednisolone, encephalopathy, anxiety, headache, and fever.

Others: There is an increased risk of developing skin and lymphoproliferative malignancies in cyclosporine-treated psoriasis patients.

• Increase in the occurrence of malignant lymphomas.
• Increase the level of inflammatory cytokines such as TNF-alfa.
• Increase the infection risk. [8][9][10]

Contraindications

Drugs: amphotericin B deoxycholate, atorvastatin, bosentan, cidofovir, elbasvir/grazoprevir, flibanserin, lomitapide, mifepristone, neomycin oral, pitavastatin, saquinavir, simvastatin, sitaxentan, tacrolimus

BCG

Attenuated vaccine

Hypersensitivity to cyclosporine or any of the ingredients of the formulation (such as polyoxyethylated castor oil)

Active infection

Patients with impaired renal function

Asthma

History of blood dyscrasias

Uncontrolled hypertension

In the case of psoriasis: Concomitant PUVA therapy, ultraviolet B (UVB) radiation, coal tar, methotrexate, other immunosuppressants [11]

Monitoring

The patient's BUN creatinine ratio, magnesium levels, and blood pressure require monitoring while on therapy. Uric acid monitoring is debatable. Therapeutic monitoring of cyclosporine in transplant patients is a valuable tool in adjusting drug dosage to prevent acute rejection, nephrotoxicity, and predictable dose-dependent adverse reactions. The ideal therapeutic range of cyclosporine in whole blood is as follows: 

Kidney transplant: 200 to 400 ng/ml in the first week after transplantation; 125 to 275 ng/ml in the second week to the sixth-month post-transplantation; 100 to 150 ng/ml in the seventh to the twelfth-month post-transplantation; and 75 to 160 ng/ml one year after transplantation (residual concentration predose).

Heart transplant: 250 to 350 ng/mL in the first six months; 100 to 200 ng/mL six months to one year after transplantation (residual concentration predose).

Liver transplant: 250 to 350 ng/mL for the first six months; 100 to 200 ng/mL six months to one year after transplantation (residual concentration predose).

The range between effective cyclosporine concentrations and the concentrations associated with serious toxicity is fairly narrow. Sub-optimal doses or concentrations can lead to therapeutic failure or severe toxicity. Cyclosporine is subject to therapeutic monitoring based on pharmacokinetics measures. The medication has low-to-moderate within-subject variability.

Toxicity

In the event of toxicity, establishing a patent airway is a priority. There is a need to watch for signs of respiratory insufficiency and provide ventilation assistance if needed. Also, the healthcare provider needs to monitor for shock and treat if necessary. They should anticipate seizures and treat if necessary, and initiate supportive and symptomatic treatment. When overdosage occurs in patients prescribed cyclosporine therapy, the healthcare provider may withhold the drug for a few days or initiate alternate-day therapy until the patient stabilizes.[12]

Hemodialysis only eliminates 1% of the dose. Monitoring serum CsA levels is mandatory, and patients may need multiple dose adjustments during the treatment period. The CVC (central venous catheter) line is not used to infuse CsA and can be safely used to collect blood samples for serum CsA levels. The procedure can be performed immediately after interrupting the infusion if using the appropriate technique for discarding 5 mL of blood.

Drugs that can decrease CsA levels include rifampicin, rifabutin, isoniazid, barbiturates, phenytoin, carbamazepine, intravenous trimethoprim, intravenous sulfadimidine, imipenem, cephalosporins, terbinafine, ciprofloxacin, ticlopidine, octreotide, and nefazodone. Conversely, drugs that can increase CsA levels include verapamil, diltiazem, amlodipine, nicardipine, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, azithromycin, saquinavir, indinavir, nelfinavir, ritonavir, methylprednisolone.

Enhancing Healthcare Team Outcomes

Cyclosporine is a widely used immunosuppressive drug, especially in transplant patients. The majority of patients on cyclosporine can be followed as outpatients by the nurse practitioner, primary care provider, internist, and specialist. The clinical staff must monitor cyclosporine levels regularly to prevent acute rejection, nephrotoxicity, and predictable dose-dependent adverse reactions.

Further, the pharmacist and nurse should educate the patient on potential complications of the drug and the need to follow up regularly. Pharmacists should verify dosing, and also, given the extensive drug-drug interaction list for cyclosporine, thorough medication reconciliation is in order, with any red flags reported promptly to the rest of the healthcare team. Nursing can monitor both for treatment effectiveness and the adverse effects of the medication, alerting the treating physician of any concerns. Finally, patients on cyclosporine are at a slight risk of lymphoproliferative malignancies and infections; thus, a thorough history and physical exam are vital at each clinic visit.

Cyclosporine therapy has a much higher opportunity for patient success with the communication and collaboration of an interprofessional healthcare team. [Level 5]