Sandimmun Neoral Mechanism of Action

Pharmacotherapeutic Group: Selective immunosuppressive agent. ATC Code: L04AA01.
Pharmacology: Pharmacodynamics: Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent which, in animals, prolongs survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease (GVHD) and also T-cell-dependent antibody production. At the cellular level, it inhibits production and release of lymphokines including interleukin 2 (T-cell growth factor, TCGF). Ciclosporin appears to block the resting lymphocytes in the G₀ or G₁ phase of the cell cycle and inhibits the antigen-triggered release of lymphokines by activated T-cells.
All available evidence suggest that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress hemopoiesis and has no effect on the function of phagocytic cells. Patients treated with Sandimmun are less prone to infection than those receiving other immunosuppressive therapy.
Successful solid organ and bone marrow transplantations have been performed in man using Sandimmun to prevent and treat rejection and GVHD. Beneficial effects of Sandimmun therapy have also been shown in a variety of conditions that are known, or may be considered, to be of autoimmune origin.
Pharmacokinetics: Sandimmun Neoral is a new pharmaceutical form of the active ingredient ciclosporin based on the microemulsion principle, which reduces the variability of pharmacokinetic parameters and provides dose linearity of ciclosporin exposure with a more consistent absorption profile and less influence from concomitant food intake. The formulation is a microemulsion preconcentrate, which in pharmacokinetic and clinical studies has demonstrated that the correlation between trough concentration and exposure to ciclosporin is much stronger when ciclosporin is given as Sandimmun Neoral than when it is given as Sandimmun. The formation of the microemulsion itself takes place in the presence of water, either in the form of a beverage or in the form of gastric fluid.
When Sandimmun Neoral is given, it provides improved dose linearity in ciclosporin exposure (AUC_B), a more consistent absorption profile and less influence from concomitant food intake and from diurnal rhythm than does Sandimmun. These properties combined yield a lower within-patient variability in pharmacokinetics of ciclosporin and a stronger correlation between trough concentration and total exposure (AUC_B). As a consequence of these additional advantages, the time schedule of Sandimmun Neoral administration need no longer take that of meals into account. In addition, Sandimmun Neoral produces a more uniform exposure to ciclosporin throughout the day and from day to day on a maintenance regimen.
Sandimmun Neoral soft gelatine capsules and Sandimmun Neoral oral solution are bioequivalent. The data available indicate that following a 1:1 conversion from Sandimmun to Sandimmun Neoral, trough concentrations in whole blood are comparable, thereby remaining in the desired therapeutic trough level range. Compared to Sandimmun (with which peak blood concentrations are achieved within 1-6 hrs), Sandimmun Neoral is more quickly absorbed (resulting in a 1 hr earlier mean t_max and a 59% higher mean C_max) and exhibits, on average, a 29% higher bioavailability.
Ciclosporin is distributed largely outside the blood volume. In the blood, 33-47% is present in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Ciclosporin is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug.
There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and on the target population. The terminal half-life ranged from 6.3 hrs in healthy volunteers to 20.4 hrs in patients with severe liver disease.
Toxicology: Preclinical Safety Data: Ciclosporin gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams were adverse effects seen in reproduction studies in rats. At toxic doses (rats at 30 mg/kg and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and fetotoxic as indicated by increased prenatal and postnatal mortality and reduced fetal weight together with related skeletal retardations. In the well-tolerated dose range (rats up to 17 mg/kg and rabbits up to 30 mg/kg/day orally), ciclosporin proved to be without any embryolethal or teratogenic effects.
Carcinogenicity: Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4 and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2 and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose-related.
No impairment of fertility was demonstrated in studies in male and female rats.
Ciclosporin has not been found mutagenic/genotoxic in the Ames test, the V79-HGPRT test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay and the DNA repair test in sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by ciclosporin using human lymphocytes in vitro gave indication of a positive effect (ie, induction of SCE) at high concentrations in this system.
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies during ciclosporin treatment is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause the lesions to regress.