Cyclosporine is a cyclic polypeptide calcineurin inhibitor with immunosuppressant properties that is used for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation patients, for the prevention of graft rejection in solid organ transplant patients, and for the treatment of psoriasis, rheumatoid arthritis, and a variety of other autoimmune diseases.1,2, and 3 The immunomodulating properties of cyclosporine are due to its ability to block the production of interleukin-2 and other cytokines secreted by T lymphocytes.1,2, and 3 Cyclosporine binds to cyclophilin, an intracellular cytoplasmic protein found in T cells. The cyclosporine-cyclophilin complex interacts with calcineurin, inhibits the catalytic activity of calcineurin, and prevents the production of intermediaries involved with the expression of genes regulating the production of cytokines.
THERAPEUTIC AND TOXIC CONCENTRATIONS
The therapeutic range of cyclosporine used by clinicians varies greatly according to the type of assay used to measure cyclosporine and whether blood or serum concentrations are determined by the clinical laboratory (Table 18-1).1,3,4, and 5 Because cyclosporine is bound to red blood cells, blood concentrations are higher that simultaneously measured serum or plasma concentrations. High-pressure liquid chromatography (HPLC) assay techniques are specific for cyclosporine measurement in blood, serum, or plasma. However, older polyclonal immunoassays are nonspecific and measure both cyclosporine and its metabolites. Newer monoclonal immunoassays (various) are now available that are relatively specific for cyclosporine and produce results similar to the HPLC assay. As a result, cyclosporine concentrations measured simultaneously in a patient using the specific high pressure liquid chromatography technique or one of the specific immunoassays will be lower than that determined using a nonspecific immunoassay. Since cyclosporine metabolites are excreted in the bile, liver transplant patients who are immediately posttransplant surgery can have very high cyclosporine metabolite concentrations in the blood, serum, and plasma because bile production has not begun yet in the newly transplanted organ. If nonspecific immunoassays are used to measure cyclosporine concentrations in liver transplant patients immediately after surgery before the graft has begun to produce bile, the predominate species measured with this assay methodology may be cyclosporine metabolites and not cyclosporine. One reason some laboratories favor the use of immunoassays for the measurement of cyclosporine concentrations, even though they are less specific for the parent compound, is that it takes less time to conduct the technique so that cyclosporine concentrations can be returned to clinicians more rapidly. For the purposes of the pharmacokinetic calculations and problems presented in this book, cyclosporine concentrations in the blood using the cyclosporine-specific high-pressure liquid chromatograph assay results will be used.
TABLE 18-1Cyclosporine Therapeutic Concentrations for Different Assay Techniques and Biologic Fluids |Favorite Table|Download (.pdf) TABLE 18-1 Cyclosporine Therapeutic Concentrations for Different Assay Techniques and Biologic Fluids
|Assay ||Biologic Fluid ||Therapeutic Concentrations (ng/mL) |
|High-pressure liquid chromatography (HPLC), monoclonal immunoassay ||Blood ||100-400...|