Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is subject to considerable interindividual variation.

Cyclosporin clinical pharmacokinetics

OBJECTIVE\nLow-dose prednisone given on alternate days as a steroid adjunct to cyclosporine therapy was investigated primarily for its influence on kidney graft and patient survival and, secondarily, on renal function and complications.\n\n\nDESIGN\nMulticentre randomized double-blind clinical trial.\n\n\nSETTING\nFourteen Canadian transplant centres.\n\n\nPATIENTS\nA total of 523 patients with well-functioning renal transplants (cadaveric grafts or grafts from living related donors) and without active graft rejection reactions who were entered into the trial from 1982 to 1985.\n\n\nINTERVENTION\nPatients were randomly assigned 90 days after transplantation to receive either placebo (260 patients) or low-dose prednisone (263 patients).\n\n\nMAIN OUTCOME MEASURES\nGraft and patient survival.\n\n\nMAIN RESULTS\nAfter at least 5 years of follow-up 50 patients assigned placebo had lost their graft and 17 had died; the corresponding figures for those assigned prednisone were 38 and 16. After an average interval of 1.4 years 143 patients in the placebo group and 123 patients in the prednisone group had stopped therapy with the test drug or had had their treatment group decoded or both. Patients were withdrawn from the study 2 years after stopping the test therapy. The actuarial 5-year graft survival rates were 73% and 85% in the placebo and prednisone groups respectively (p = 0.03), and the actuarial 5-year patient survival rates were 92% and 94% respectively (p = 0.6). This analysis included 43 and 29 graft losses and 14 and 12 deaths in the placebo and prednisone groups respectively. Weibull parametric modelling of graft survival identified the following variables as risk factors for graft loss: histocompatibility leukocyte antigen B (HLA-B) mismatching (p = 0.007), donor death from cerebrovascular accident (p = 0.01), increased donor age (p = 0.02) and being a male recipient (p = 0.05). When these factors were included in the Cox proportional hazards model, the influence of assigned treatment on graft survival was reduced to p = 0.1. Donor death from cerebrovascular accident (p = 0.002), diabetes mellitus in the recipient (p = 0.02) and increased recipient age (p = 0.05) were risk factors for patient death. Renal function and incidence of complications were similar in the treatment groups.\n\n\nCONCLUSIONS\nContinued administration of low-dose prednisone on alternate days is advisable, particularly in patients with cadaveric grafts and those with previously failed transplants.

Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts

Optimal Use of Sandimmun® in Organ Transplantation

SUMMARY

The use of the drug cyclosporin is limited by toxicity. It would be advantageous to develop therapeutic monitoring of cyclosporin which would predict the development of clinical toxicity. In the present study, alternative methods of measuring cyclosporin levels were evaluated in a heterogenous population of transplant patients, comparing a fluorescent polarization immunoassay using a non-specific polyclonal antibody, which measures both cyclosporin and its main metabolites, and a specific high-performance liquid chromatography assay for unchanged cyclosporin in blood.



Neither measured variable alone correlated with laboratory evidence of renal toxicity (serum creatinine) or liver toxicity (serum glutamate transaminase, lactic dehydrogenase, alkaline phosphatase, or serum bilirubin). The relationship between metabolites and parent cyclosporin was quantitated using the ratio of cyclosporin levels determined by fluorescent polarization immunoassay over levels determined by high-performance liquid chromatography. A cohort of patients with markedly elevated ratios of cyclosporin were identified. When patients’data were reviewed collectively and individually there was a correlation between an elevated ratio and the serum bilirubin (r= 0.41, P < 0.001). This association could be either due to cyclosporin as a cause of cholestasis or to cholestasis from any cause resulting in netaboite accumulation. Further studies are needed to clarify the role of cyclosportin in hepatic dysfunction and develop erly, specific markers for this cyclosporin-associated toxicity.

Cholestasis in transplant patients--what is the role of cyclosporin?

The potential replacement of HPLC by 125I-RIA for the characterization of cyclosporin A: a bioavailability study after oral administration in healthy human subjects

Pharmacokinetics of cyclosporine in solid organ transplantation.

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Pharmacokinetics of cyclosporine in solid organ transplantation.