Cyclosporine

Cyclosporine is a powerful immunosuppressant that is given to organ transplant recipients to minimize rejection. It suppresses T-helper cell activation by inhibiting calcineurin and interleukin-2 production.

Oral availability is highly variable, ranging from 10 to 70% due to incomplete absorption from the gut. Almost 80% of cyclosporine is sequestered in red blood cells.

Plasma levels peak in 2 to 4 hours. Cyclosporine is metabolized predominantly in the liver by the hepatic cytochrome P-450 system. Metabolites are eliminated in the bile. Less than 3% of the parent drug is eliminated in the urine. The circulating half life is 8 to 24 hours and may be prolonged in patients with liver, but not renal, disease.

The most severe complication of cyclosporine therapy is renal toxicity. Other adverse effects include hypertension, convulsions, tremors, pulmonary edema, and an increased risk of lymphoma. 

Cyclosporine also has significant interactions with other drugs frequently given to transplant recipients. Drugs that enhance the potential toxicity of cyclosporine, include aminoglycoside antibiotics, amphotericin B, acyclovir, ketoconazole, lovastatin, NSAIDs, and ranitidine. Drugs that inhibit CYP3A3 and CYP3A4 raise cyclosporine levels by decreasing biotransformation. Examples include methylprednisolone, amphotericin B, cimetidine, amiodarone, fluoxetine, protease inhibitors, erythromycin, and grapefruit juice. Agents that increase hepatic metabolism result in lower cyclosporine levels (phenobarbital, phenytoin, carbamazepine, rifampin, trimethoprim, and St John's wort). 

Optimal dosing is difficult because absorption, distribution, metabolism, and excretion vary widely, and are affected by altered gastrointestinal and liver function. Dosages must be individualized to maintain cyclosporine levels within a narrow therapeutic window. Low doses do not adequately suppress the immune system, while high doses produce toxic effects. 

Therapeutic ranges are based on trough levels and vary according to the type of allograft, risk of rejection, concomitant drug therapy, and risk of toxicity. A steady state is usually reached about two months after transplantation. The target therapeutic range is typically between 100 and 400 ng/mL. Recommended therapeutic ranges for different types of organ transplantation are listed in the following table.

The preferred method for measuring cyclosporine is liquid chromatography tandem mass spectrometry (LC-MS-MS). Some immunoassays also detect cyclosporine metabolites and give results that are approximately 30% higher than LC/MS-MS

Specimen requirement is one 5 mL lavender top (EDTA) tube of blood.

In addition to cyclosporine trough levels, other laboratory parameters should also be followed including; CBC, serum electrolytes, BUN, creatinine, magnesium, and urinalysis.  

References

Tedesco D, Haragsim L. Cyclosporine: a review. J Transplant. 2012;2012:230386.

Graham RM, Cyclosporine: mechanisms of action and toxicity, Cleve Clin J Med, 1994;61(4):308-313.