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Spring 1994Volume 1, Number 1 |
Mycophenolate mofetil (RS-61443) is a derivative of mycophenolic acid (MPA) with improved bioavailability. Produced by Syntex Laboratories, mycophenolate mofetil, like azathioprine, inhibits nucleic acid synthesis. Azathioprine competitively inhibits purine synthesis, while MPA blocks the de novo pathway of guanosine nucleotide synthesis by inhibiting the activity of inosine monophosphate dehydrogenase. Both T and B lymphocytes are highly dependent upon the de novo pathway, whereas other cells utilize the salvage pathway of nucleotide synthesis. As a result, MPA selectively inhibits lymphocyte activity. MPA also inhibits the glycosylation of adhesion molecules and the binding of activated lymphocytes to activated endothelial cells, thus limiting recruitment of lymphocytes into sites of active rejection.
Mycophenolate mofetil has been used successfully in canine and rodent models for kidney, heart, and pancreatic islet cell transplantation. Graft survival has been increased, and acute rejection has been prevented and reversed in several trials. Significant nephrotoxicity and hepatotoxicity have not been seen. Lymphopenia has been reported in monkeys but not in dogs. Gastrointestinal complications, including gastritis and diarrhea, have been common.
In a dose-ranging open-label study, 43 patients received mycophenolate mofetil 200-1000 mg/day or placebo in combination with cyclosporin A (CSA) following cadaveric renal transplantation. No difference in the rejection rate was seen, probably due to the low doses used. In another open-label trial in recipients of cadaveric renal transplants, 49 patients were enrolled into seven groups. Each group received Minnesota antilymphocyte globulin (MALG), methylprednisolone, and CSA, as well as mycophenolate mofetil in doses ranging from 100-3500 mg/day. Follow-up ranged from 14 to 26.5 months (mean: 19.5 months). The 18-month actuarial patient and allograft survivals were 100% and 95%, respectively. Only four acute rejections occurred, and all four responded to treatment. In another trial, 3 of 4 liver transplant recipients on cyclosporine or tacrolimus regimens were successfully switched to mycophenolate mofetil following neurotoxic reactions to their primary immunosuppressive agents.
Mycophenolate mofetil has also been used in solid organ transplant recipients experiencing refractory rejection. In a multicenter trial, 52 of 75 (69%) such patients with renal transplants had resolution following mycophenolate mofetil in doses of 2000-3000 mg/day, with follow-up durations of 8 to 18 months. In patients with serum creatinines <4.0 mg/dL, the success rate was 79%. In another trial of 26 renal transplant patients with refractory rejection, mycophenolate mofetil 2000-3500 mg/day was administered. With a mean follow-up of 20 months, the 12-month actuarial patient and graft survivals were 91% and 54%, respectively. Twenty-one of 23 orthotopic liver transplant recipients experiencing refractory acute rejection responded to mycophenolate mofetil at follow-up durations of 5 to 11 months (mean: 7.2 months). Of the 21 responders, 14 resolved and 7 improved. Only two patients required retransplantation, one for chronic and one for acute rejection. However, none of four liver transplant patients with chronic rejection responded to mycophenolate mofetil. In another open-label trial of 30 heart transplant recipients experiencing biopsy-documented mild acute rejection, mycophenolate mofetil 500-3000 mg/day was substituted for azathioprine or cyclophosphamide for an eight-week period. Rejection resolved within four weeks in 20 of the 30 patients. Progression to moderate rejection was noted in 2 of 6 (33%) patients receiving mycophenolate mofetil 500 mg/day, but in only 2 of 24 (8%) of those receiving >1000 mg/day (p=0.10).
Clinical trials with mycophenolate mofetil have consistently shown a low incidence of significant adverse effects. Nephrotoxicity, neurotoxicity, and hepatotoxicity have not been directly attributed to the drug. Occasional cases of neutropenia have been reported, but hematologically, mycophenolate mofetil is much better tolerated than azathioprine. Other than infection, an expected complication of any immunosuppressive therapy, the most frequent side effects of mycophenolate mofetil are gastrointestinal, especially nausea, vomiting, diarrhea, and gastritis. In most cases these reactions have responded to dose reduction or to administration of the drug three times daily rather than twice daily.
Mycophenolate mofetil is a promising immunosuppressive agent. Further trials are needed to determine its ultimate role in the management of transplant recipients.
Emmanuel Saltiel, PharmD
Cedars-Sinai Medical Center
Los Angeles, California
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