Clinical Use of the Calcineurin Inhibitors 6.1

Transplantation 6.1.1

Maintenance Immunosuppression

The introduction of the original Sandimmun (or Sandimmune) formulation of ciclosporin as a clinical immunosuppressant for renal transplantation was associated with a marked improvement in patient and graft survival (Canadian Multicenter Transplant Study Group 1983; European Multicentre Trial Group 1983). In the Canadian trial, ciclosporin and prednisone were compared to azathioprine and prednisone; in the European study, ciclosporin monotherapy was compared to azathioprine plus steroids. However, in the Canadian trial, serum creatinine levels were higher in the ciclosporin group, suggesting nephrotoxicity; and in the European study, 24 of 84 patients in the ciclosporin group who had functioning grafts were switched to conventional immunosuppression because of nephrotoxicity. These early studies established ciclosporin as a more effective immunosuppressive agent while illustrating the problem of nephrotoxicity.

The results of liver and heart transplantation were both improved following the introduction of ciclosporin, although once again renal function was found to be worse in the heart transplant patients who received ciclosporin (Starzl et al. 1981; Oyer et al. 1983; Emery et al. 1986). The availability of ci-closporin was one of the factors that enabled lung transplantation to be pert-

complex that inhibits calcineurin. They thereby prevent the dephosphorylation of NFAT and hence the expression of IL-2 and other genes. It is believed that many of the toxic non-immunosuppressive effects of the ciclosporin and tacrolimus are related to the effect of calcineurin inhibition on the function of other regulatory proteins formed successfully (Reitz et al. 1982; Toronto Lung Transplant Group 1986).

The use of ciclosporin gradually evolved with lower dose regimens being introduced in combination with other immunosuppressive agents and the development of dose adjustment according to the concentration of ciclosporin present in the patient's blood (therapeutic drug monitoring, TDM). The aim of combination therapy was to obtain synergistic immunosuppression by using drugs that act at different stages of the T cell activation cascade but which have non-overlapping toxicities (Fig. 2) (Banner and Lyster 2003).

The introduction of tacrolimus for organ transplantation made its greatest impact in the field of liver transplantation. Absorption of the Sandimmun formulation of ciclosporin is dependent on bile flow. Early after liver transplantation, when a T-tube biliary diversion is normally in place, Sandimmun was not absorbed effectively, necessitating intravenous therapy. In contrast, oral therapy with tacrolimus can be established early after liver transplantation. Clinical trials found that the use of tacrolimus, when compared with Sandimmun, was associated with lower acute rejection rates, including corticosteroid-resistant rejection, and similar graft and patient survival (European FK506 Multicentre Liver Study Group 1994; U.S. Multicenter FK506 Liver Study 1994). In renal transplantation, tacrolimus use was again associated with lower rates of rejection (Vincenti et al. 1996; Mayer et al. 1997; Jensik 1998; Knoll and Bell 1999). In heart transplantation, a tacroli-mus-based immunosuppression regimen had a similar efficacy to one based on ciclosporin but with a different profile of side effects (Taylor et al. 1999).

Based on data indicating that pharmacokinetic variability associated with the Sandimmun formulation of ciclosporin was a factor limiting efficacy (Lindholm and Kahan 1993; Kahan et al. 1996), a new formulation of ciclosporin (Neoral) was introduced. Direct comparison of the two formulations in heart transplant recipients showed similar safety together with graft and patient survival rates, while there was a reduction in the incidence of steroid-resistant rejection (Eisen et al. 2001).

Due to the very different potency and pharmacokinetic profiles of ci-closporin and tacrolimus together with the need for TDM (which necessitates 'open label' clinical trials), it has not been possible to establish a clear advantage for one agent over the other except in specific circumstances. There are, however, differences in the side effects of the two CNIs.

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