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Spring 1997Volume 4, Number 1 |
Over the last three years, two new immunosuppressive agents, tacrolimus (Prograf®, Fujisawa USA) and mycophenolate mofetil (CellCept®, Roche Laboratories), and one reformulated product, the microemulsion formula of cyclosporine A (Neoral®, Sandoz Pharmaceuticals), were introduced into clinical transplantation. Recent controlled clinical trials have demonstrated the efficacy of all three agents. In particular, tacrolimus and mycophenolate mofetil are superior to conventional immunosuppression in reducing the incidence of acute rejection. Several national and international trials have shown the microemulsion formula of cyclosporine A to be superior to standard cyclosporine A in both absorption and area under the concentration curve (AUC).
Neoral was approved in August of 1995 for use in clinical transplantation. The microemulsion formula improves the absorption of cyclosporine A and decreases both interpatient and intrapatient variability of cyclosporine levels.1 Neoral is associated with a higher Cmax, a shorter Tmax, and increased AUC over Sandimmune therapy. The major clinical benefit of Neoral is in patients who are poor absorbers of cyclosporine A; Neoral therapy produces an improved early absorption of the drug and more predictable pharmacokinetics.2 Nevertheless, no clinical advantage in reducing episodes of acute rejection or the incidence of chronic rejection has been demonstrated.3 A retrospective correlation of poorer cyclosporine absorption and the development of chronic rejection suggests that the new microemulsion formula might help reduce the incidence of chronic rejection in the future.4
Mycophenolate mofetil was also approved in mid-1995 for use in combination with cyclosporine A and prednisone for the prevention of acute renal allograft rejection. This approval was based on the results of three separate international trials with 1497 patients which convincingly demonstrated a nearly 50% reduction in the incidence of acute rejection in the early postoperative period.5-7 Moreover, the drug was not associated with a significant increase in opportunistic infections or malignancy. In addition, the use of OKT3 (Ortho Biotech) for the treatment of refractory rejection was statistically significantly lower in the mycophenolate treatment arms than in the groups who received conventional immunosuppression. The obvious hope was that the observed decrease in acute rejection would lead to a decreased incidence of chronic rejection. While long-term data are still being collected, one-year graft survival has not been improved with the use of mycophenolate mofetil. This failure to improve one-year graft survival has led to questions about the appropriateness of the long-term use of mycophenolate mofetil, since long-term graft survival may not be enhanced.
Mycophenolate mofetil is also effective as a rescue agent for refractory rejection.8 A multicenter clinical study of 150 kidney transplant patients with refractory rejection showed a decreased incidence of patient and graft loss and recurrent episodes of rejection following treatment with mycophenolate. However, these results were not statistically significant. Studies are continuing in heart and liver transplant patients to determine the role of mycophenolate mofetil in these solid organ groups.
At the University of Wisconsin Medical Center, we have used mycophenolate mofetil in conjunction with prednisone and Neoral as our primary therapy for renal allograft recipients. Since August of 1995, we have achieved a one-year actuarial graft survival of 94% with a rejection incidence of 27% in primary cadaver transplant recipients. The results are even more dramatic in kidney-pancreas transplants, with a 50% reduction of acute rejection from 70% in the pre-mycophenolate era to 30% currently. The use of OKT3 antibodies for reversal of rejection decreased from 37% to 9%. From these and other data it is clear that mycophenolate mofetil provides a major improvement in the immunosuppressive armamentarium, although its long-term benefits remain to be proven.
A multicenter study of tacrolimus in kidney transplantation has recently been completed.9 This was a randomized phase III study of tacrolimus versus cyclosporine immunosuppression in kidney transplantation. Although overall patient and graft survivals were similar, biopsy-proven acute rejection occurred in 30.7% of tacrolimus-treated patients versus 46.4% of cyclosporine-treated patients (p<0.01). The use of antilymphocyte antibodies was reduced from 25% in the cyclosporine treatment arm to 10.7% in the tacrolimus-treated recipients. In addition, a blinded review of the biopsies showed significantly decreased severity of acute rejection with tacrolimus compared with cyclosporine.
| SUMMARY OF NEW IMMUNOSUPPRESSIVE AGENTS | ||||
| New agent | Reduction in acute rejection | Improved one-year graft survival | Increased opportunistic infection | Major toxicity |
| Mycophenolate mofetil | Yes | No | Slight | GI Leukopenia |
| Tacrolimus | Yes | No | No | Diabetes Neurotoxicity |
| Neoral | No | No | No | Neurotoxicity GI |
The major side effect associated with tacrolimus was diabetes, which occurred in 19.9% of patients at 12 months, but decreased to 12.6% by 18 months. In the cyclosporine group, the incidence of diabetes was 4% at 12 months and 3.3% at 18 months. Other side effects associated with tacrolimus were a greater incidence of deep venous thrombophlebitis and neurotoxicity. There was no difference in the incidence of nephrotoxicity or hypertension between cyclosporine and tacrolimus.
A significant benefit of tacrolimus therapy was a marked decrease in the incidence of hyperlipidemia. Levels of total cholesterol, LDL, triglycerides, and the use of lipid-reducing medications were significantly lower throughout the study period for tacrolimus-treated recipients. The results of this study, although showing no differences in patient and graft survivals, suggested that tacrolimus was superior in reducing the incidence of acute rejection and antilymphocyte therapy in kidney transplant recipients.
The introduction of these three agents in clinical transplantation increases the available options for post-transplant immunosuppression. Several questions remain to be answered. The first is whether the increased efficacy of these agents will allow discontinuation of corticosteroids. There is near universal agreement in the transplant community that corticosteroids, although a mainstay of immunosuppression for decades, cause the greatest long-term morbidity for transplant recipients. Similarly, the introduction of mycophenolate mofetil may allow reduction in cyclosporine or tacrolimus usage, both of which can cause long-term nephrotoxicity. Finally, the role of combination therapy with mycophenolate mofetil and tacrolimus remains to be defined. A recent study from The University of Miami suggests that the AUC for mycophenolic acid may be increased when used in combination with tacrolimus, which could result in increased toxicity.10 Despite these questions, the increased therapeutic options available to the transplant community may result in decreased morbidity related to acute rejection episodes and an improvement in late renal allograft survival.
John D. Pirsch, MD
Associate Professor of Medicine and Surgery
Director, Medical
Transplantation Service
University of Wisconsin
Madison, Wisconsin
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