Cyclosporine A

Source and Pharmacology

Cyclosporine A (also called CSA, Cyclosporin A, Sandimmune, NSC #290193) is a cyclic polypeptide antibiotic consisting of eleven amino acids. Its major metabolites are cyclosporin A and cyclosporin C. It is a potent immunosuppressive agent that prolongs survival of allogeneic bone marrow and organ transplants. Current evidence suggest that CSA selectively inhibits IL-2 stimulated proliferation of activated T-lymphocytes. CSA has been shown in vitro to be a potent inhibitor of P-glycoprotein that causes multidrug resistance to natural-product antineoplastic agents. The terminal half-life of CSA is approximately 19 hours (range 10-27 hours). Ninety-nine percent of CSA is metabolized. Elimination is primarily biliary with approximately 6% excreted in the urine. The volume of distribution varies from 3.5 L/kg to 13 L/kg with higher concentrations of the drug found in the liver, pancreas, and fat. CSA clearance rates have been shown to be higher in pediatric patients and patients <25 years old. Drugs that stimulate or inhibit hepatic P-450 enzymes may alter clearance of CSA.

Toxicity

(L) = Toxicity may also occur later.

Formulation and Stability

CSA is available as a 5-mL ampule (50 mg/mL) in a polyoxyethylated castor oil vehicle (Cremophol EL) with 32.9% alcohol. Ampules should be stored below 30_C and protected from light and freezing. Concentrated CSA for injection has to be further diluted immediately prior to administration. One mL of the drug is diluted in 20-100 mL of 0.9% sodium chloride or D₅W. For the purpose of the short 3-hour infusions in this protocol, we recommend diluting 1 mg of CSA in 2 mL of 0.9% sodium chloride. For prolonged infusions, D₅W is the preferred intravenous fluid rather than 0.9% sodium chloride, which causes a 7-8% loss of activity over 24 hours. After dilution, CSA is stable for 24 hours in glass bottles. It is not necessary to protect the reconstituted CSA from light.

Guidelines for Intravenous Administration

Intravenous infusion in glass bottles or in polyolefin lined bags and lines. Non-polyvinyl chloride tubings should be used, commonly available for nitroglycerine infusions. CSA should be infused separately from the chemotherapy since they are incompatible. Therefore, for the purpose of this protocol, one-third of the total CSA dose is given in the central line over one hour, then the chemotherapy is given over 30 minutes, and then the balance of the CSA is given over two hours.

Monitor closely for the first 30 minutes and at frequent intervals thereafter for acute allergic reactions. We have found that diluting CSA in large volumes of intravenous fluids and premedication with diphenhydramine and hydrocortisone help prevent anaphylactic reactions. ìAnaphylactoidî reactions may be caused by insufficient mixing of the Cremophol EL vehicle of CSA in intravenous fluid, thereby resulting in a ìbolus injectionî of Cremophol EL. ìAnaphylactoidî reactions are not true allergic reactions and can be prevented by thoroughly mixing the Cremophol EL vehicle of CSA in a large volume of intravenous fluid [Theis 1995].

Drug Procurement

CSA is commercially available.  See the package insert for further information.