Cyclosporine

Article Author:
Carolina Tapia
Article Editor:
Mark Pellegrini
Updated:
10/27/2018 12:31:30 PM
PubMed Link:
Cyclosporine

Indications

Cyclosporin is an immunosuppressive agent used to treat organ rejection post-transplant. It is also used for certain other autoimmune diseases.

In solid organ transplantation, it is used for the treatment of organ rejection in kidney, liver, and heart allogeneic transplants.

In patients with rheumatoid arthritis, it is indicated when the disease has not adequately responded to methotrexate.

For psoriasis, it is indicated for the treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have not responded to at least one systemic therapy.

In patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), cyclosporin is used to treat amyotrophic lateral sclerosis and its variants.

In nephrotic syndrome, it is indicated to treat focal segmental glomerulosclerosis not responding to corticosteroids.

In individuals with graft vs host disease (GVHD), it prevents and treats the disease.

In the case of uveitis, cyclosporin is indicated for refractory posterior uveitis and Behcet's disease.

Non- FDA Approved indications include:

  • Allergic conjunctivitis, keratoconjunctivitis, Langerhans cells histiocytosis, ocular graft vs host disease, autoimmune hepatitis, Duchenne muscular dystrophy, ulcerative colitis, pure red cell aplasia, Henoch Schonlein purpura nephritis

Mechanism of Action

Cyclosporine has been demonstrated to suppress cell-mediated immune reactions. No effects on phagocytic function have been detected in animals, and it does not cause bone marrow suppression in animal or human models.

The mechanism of action of cyclosporine is as a Calcineurin Inhibitor, a Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor. Cyclosporin A (CsA) inhibits the synthesis of interleukins (IL), including IL-2 which is essential for self-activation 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 T-suppressor cells may also be suppressed. The LT-B-lymphocyte (LB) co-operation is essential for activation of LB; the latter is also inhibited. It has been showed that CsA had an inhibiting effect on CD4+ CD25+ Tregs, which might block the host immune tolerance potentiality

Metabolism: Via hepatic CYP3A4

Metabolites: In humans, cyclosporin A is predominantly metabolized into a pair of hydroxylated derivatives (AM1 and AM9), and one N-methylated derivative (AM4N).

Enzymes inhibited: CYP3A4 and P-glycoprotein

Half-Life: 8.4-27 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 recipients of renal or liver allografts, appears to be somewhat slower in cardiac transplant patients.

Excretion: Mainly bile and feces

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

Administration

Dosing for Organ Transplant in Adults

Oral

  • Four to 12 hours pre-transplant: 14 to 18 mg/kg by mouth for 1 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 1 dose over 2 to 6 hours
  • Post-transplant, until the patient can tolerate oral therapy: 2 to 10 mg/kg IV once per day

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 8 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 4 weeks if the response has not been effective. Maximum dose: 4 mg/kg per day

Adjust dosage according to trough levels.

Adverse Effects

Adverse effects include:

  • Cardiovascular: hypertension, arrhythmia
  • Renal System: 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 are correlated with duration of treatment an 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 for the development of 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.

Contraindications

 Contraindications to cyclosporin include:

  • 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 case of psoriasis: Concomitant PUVA therapy, ultraviolet B (UVB) radiation, coal tar, methotrexate, other immunosuppressants

Monitoring

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 as follows: 

Kidney transplant: 200 to 400 ng/ml in the first week of post-transplantation; 125 to 275  ng/ml in the second week to the sixth month of post-transplantation; 100 to 150 ng/ml in the seventh to twelfth month of post-transplantation; and 75 to 160 ng/ml 1 year after post-transplantation (residual concentration predose)

Heart transplant: 250 to 350 ng/mL on the first 6 months; 100 to 200 ng/mL in 6 months to 1 year after post-transplantation (residual concentration predose)

Liver transplant: 250-350 ng/mL for the first 6 months; 100-200 ng/mL in the sixth month to 1 year after post-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.

Cyclosporine has low-to-moderate within-subject variability.

Toxicity

In the event of toxicity, establishing a patent airway is a priority. Watch for signs of respiratory insufficiency and provide ventilation assistance if needed. Monitor for shock and treat if necessary. Anticipate seizures and treat if necessary. Supportive and symptomatic treatment should be initiated. When overdosage occurs in patients prescribed cyclosporine therapy, the drug may be withheld for a few days or alternate-day therapy may be initiated until the patient is stabilized.

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 not used to infuse CsA can be safely used to collect blood samples for serum CsA levels. The procedure can be performed immediately after interrupting the infusion if the appropriate technique for discarding 5 mL of blood is used.

Drugs that can decrease CsA levels: Rifampicin, rifabutin, isoniazid, barbiturates, phenytoin, carbamazepine, IV trimethoprim, IV sulfadimidine, imipenem, cephalosporins, terbinafine, ciprofloxacin, ticlopidine, octreotide, and nefazodone.

Drugs that can increase CsA levels: Verapamil, diltiazem, amlodipine, nicardipine, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, azithromycin, saquinavir, indinavir, nelfinavir, ritonavir, methylprednisolone.