Mycophenolate Mofetil

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Abstract
Mycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an important enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or mycophenolic acid inhibit the proliferation of lymphocytes and the production of antibodies induced by a variety of mitogens and antigens. Mycophenolate mofetil is also active in several animal models of transplantation and has produced effects in animals that indicate that it may inhibit the chronic rejection process. Mycophenolate mofetil has been compared with azathioprine or placebo in 3 large, randomised, double-blind, multicentre trials as part of combination immu-nosuppression therapy with cyclosporin and corticosteroids. Compared with either placebo or azathioprine (1 to 2 mg/kg/day or 100 to 150 mg/day), mycophenolate mofetil 2 or 3 g/day was associated with a significantly lower proportion of patients experiencing acute rejection or treatment failure during the first 6 months after transplantation. Mycophenolate mofetil also tended to be associated with a lower proportion of patients who required a full course of antirejection therapy. However, the proportion of patients who died or who had graft loss was similar between all of the treatment groups. There are currently no data regarding the effects of mycophenolate mofetil on long term patient or graft survival, which are important clinical outcomes in assessing its place in the management of renal transplantation. Clinical trials are also needed to evaluate mycophenolate mofetil in specific patient populations (e.g. repeat renal transplant patients or highly sensitised patients), to determine its efficacy in alternative immunosuppressive protocols and to investigate its use in the transplantation of other solid organs. In summary, mycophenolate mofetil appears to be an attractive new agent in the prevention of graft rejection in renal transplant recipients that has shown superior efficacy to azathioprine. Although long term clinical outcome data are required, mycophenolate is a potentially important advance in transplant immunosuppression. Mycophenolic acid, the active metabolite of mycophenolate mofetil, is a non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH blocks the de novo synthesis of guanosine nucleotides which are necessary substrates for DNA and RNA synthesis. Unlike other cell types which can use the salvage pathway, B and T lymphocytes are dependent upon the de novo pathway for the generation of guanosine. Data from in vitro studies indicate that mycophenolic acid and/or mycophenolate mofetil inhibit mixed lymphocyte responses and human peripheral blood lymphocyte proliferation induced by a variety of mitogens and antigens. Mycophenolic acid decreases intracellular pools of guanosine triphosphate (GTP) and deoxyguanosine triphosphate (dGTP) in mitogen-stimulated human peripheral blood monocytes or T lymphocytic cell lines but has no effect on GTP concentrations in human neutrophils. Mycophenolate mofetil has been shown to have efficacy in several animal models of transplantation (including cardiac, hepatic, pancreatic islet and renal). Mycophenolate mofetil was effective in preventing rejection or reversing ongoing rejection in rodent cardiac and canine renal allograft transplantation. However, the drug was only marginally effective in concordant and was ineffective in discordant cardiac xenograft transplantation. In the rat renal allograft model, mycophenolate mofetil effectively attenuated functional, morphological and immunohistological changes (significant reductions in proteinuria, glomerulosclerosis, arterial obliteration, macrophage and lymphocyte infiltration and expression of adhesion molecules and cytokines) associated with chronic rejection. The drug has also been shown to inhibit antibody production in rats and in humans. In rodent studies, mycophenolate mofetil was associated with the induction of donor-specific tolerance to grafted atrial tissue after cardiac allograft transplantation and to grafted thyroid tissue or injected spleen cells after pancreatic islet allograft transplantation. Mycophenolate mofetil is well absorbed after oral administration and is rapidly converted to the active metabolite mycophenolic acid. The area under the plasma concentration-time curve (AUC) is generally proportional to dosage; however, there is some interpatient variation in values. The AUC and peak plasma concentration (Cmax) of mycophenolic acid are approximately 50% higher in stable renal transplant patients (>3 months post-transplantation) than in patients during the immediate post-transplant period. Mycophenolic acid is primarily eliminated (≈87%) in the urine as mycophenolic acid glucuronide; 6% is eliminated in the faeces. The mean ‘apparent’ half-life and plasma clearance of mycophenolic acid are 17.9 hours and 11.6 L/h, respectively, after oral administration. The AUC of mycophenolic acid and its glucuronide metabolite were higher in patients with renal impairment than in patients with normal renal function following single dose administration. However, the pharmacokinetic s of mycophenolic mofetil after a single dose are not altered in patients with cirrhosis. There are limited data in children but AUC and Cmax of mycophenolic acid appear to rise with increasing age. Initial noncomparative trials helped to determine the efficacy of mycophenolate mofetil and provided the appropriate dosage regimens for use in larger clinical trials. Three randomised, double-blind, multicentre trials have been conducted comparing mycophenolate mofetil with either placebo or azathioprine as part of combination therapy (with cyclosporin and corticosteroids) for the prevention of renal transplant rejection. Acute rejection or treatment failure (premature withdrawal from the study for any reason) during the first 6 months after transplantation occurred in significantly fewer patients receiving mycophenolate mofetil 2 or 3 g/day (range 30.3 to 38.8%) than either placebo (56.0%), or azathioprine 1 to 2 mg/kg/day (47.6%) or 100 to 150 mg/day (50%). The proportion of patients who required full courses of antirejection therapy (corticosteroids and/or anti-lymphocyte therapy) during the first 6 months post-transplant also tended to be lower in patients who received mycophenolate mofetil (range 21.1 to 31%) than either placebo (51.8%) or azathioprine (44.5 and 46%) recipients although the differences were not statistically significant. There were no differences between any of the treatment groups in terms of graft loss or patient survival at 6 or 12 months. There are currently no data on the effect of mycophenolate mofetil on long term patient or renal graft survival. Subgroup analysis of one multicentre study revealed that African-Americans receiving mycophenolate mofetil 3 g/day tended to have a lower rate of biopsy-proven acute rejection and/or treatment failure than those receiving 2 g/day. The use of mycophenolate mofetil in children is limited to a single report involving 14 patients. Data regarding the use of mycophenolate mofetil in the treatment of acute rejection are limited but initial results are promising. In patients with biopsy-proven rejection, mycophenolate mofetil 3 g/day was associated with a significantly lower frequency of subsequent biopsy-proven rejection or treatment failure than high dose intravenous corticosteroids (29 vs 51%). Rates of adverse events associated with mycophenolate mofetil appear to be dose related: 2 g/day is generally better tolerated than 3 g/day. Gastrointestinal (diarrhoea, vomiting), haematological and lymphatic (leucopenia, anaemia), and infectious (sepsis, opportunistic infections) events are most common. Diarrhoea and sepsis (most commonly cytomegalovirus viraemia) were slightly more common in patients receiving mycophenolate mofetil than in those receiving azathi-oprine. There was also an increased proportion of patients with leucopenia after treatment with mycophenolate mofetil 3 g/day compared with azathioprine treatment. The overall risk of malignancies associated with mycophenolate mofetil was similar to that of azathioprine. The initial recommended dosage of mycophenolate mofetil for the prevention of renal transplant rejection is lg twice daily to be initiated within 72 hours of transplantation as part of a combination regimen with cyclosporin and corticosteroids. Although dosages of up to 3 g/day have been used, they were less well tolerated than 2 g/day and there was no difference in clinical efficacy between these dosages. In patients with glomerular filtration rate <25 ml/min (1.5 L/h)/ 1.73m dosages should not exceed 2 g/day. Dosage adjustments in patients with delayed graft function are not required.