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- Bardsley-Elliot, A., Noble, S. & Foster, R.H. BioDrugs (1999) 12: 363. doi:10.2165/00063030-199912050-00005
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Mycophenolate mofetil is the morpholinoethyl ester prodrug of mycophenolic acid, an uncompetitive reversible inhibitor of the rate-limiting enzyme in de novo purine synthesis, inosine monophosphate dehydrogenase. As an antimetabolite immunosuppressant, mycophenolate mofetil has been evaluated for the prevention and treatment of acute rejection of a variety of solid organ allografts. It is generally added to post-transplant therapy regimens in place of azathioprine, and in conjunction with cyclosporin and corticosteroids.
In large, randomised controlled trials in renal and cardiac transplant recipients, mycophenolate mofetil has shown significant efficacy in reducing the incidence of acute rejection compared with azathioprine in the first year after transplantation. Whereas patient and graft survival rates are improved with mycophenolate mofetil in cardiac transplantation, significant benefits for patient or graft survival have not been demonstrated in clinical trials in renal transplant patients. Mycophenolate mofetil does, however, appear to reduce the incidence of renal graft loss due to rejection.
Mycophenolate mofetil has been shown to reverse ongoing acute rejection episodes in heart, kidney and liver transplant patients, and to improve graft function when used to treat chronic lung or heart graft vasculopathy.
The efficacy of mycophenolate mofetil immunosuppression appears to allow sparing of other immunosuppressive agents, particularly cyclosporin and corticosteroids, in selected patients.
The main adverse effects associated with oral mycophenolate mofetil are GI events, haematological toxicity (especially leucocytopenia) and an increased incidence of some types of infections relative to placebo. Lower dosages (2 g/day) are generally better tolerated than higher dosages (3 g/day).
Although mycophenolate mofetil carries a high acquisition cost relative to azathioprine, when other direct costs of treatment of organ transplant patients are considered, it appears to be a cost-effective alternative, at least during the first post-transplant year.
Conclusions: The benefits in terms of a reduction in the morbidity associated with acute organ allograft rejection indicate that mycophenolate mofetil should be considered as part of a primary therapy regimen in renal and cardiac transplant recipients, and as a treatment for reversal of acute refractory rejection in these patients. Further study is required to confirm its benefits in the transplantation of other solid organs.
Mycophenolate mofetil is the morpholinoethyl ester prodrug of mycophenolic acid (MPA), an uncompetitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH activity is the rate-limiting step in the de novo synthesis of guanosine nucleotides, a pathway essential for DNA synthesis in lymphocytes. Replicating lymphocytes are therefore arrested in S-phase. Other cells are able to recycle purine bases via a salvage pathway, and thus are not critically affected by MPA activity.
MPA at nanomolar concentrations inhibits lymphocyte proliferation in vitro. Most other replicating cell types are unaffected, although smooth muscle cell proliferation was inhibited at concentrations of 1 to 10 μmol/L. Administration of MPA to mice inhibited DNA synthesis in lymph nodes but not in other replicating cells. The generation of cytotoxic T lymphocytes able to lyse allogeneic cells was suppressed by MPA in vivo.
The depletion of guanosine nucleotide stores by MPA affects not only DNA synthesis, but also the glycosylation of adhesion molecules, potentially limiting the ability of lymphocytes to attach to and invade an allograft epithelium.
Antibody formation was inhibited by MPA in cultures of human lymphocytes and human spleen cells. MPA also restricted antibody production in rodents. Mycophenolate mofetil suppressed the humoral immune response to equine-derived antithymocyte and murine antilymphocyte preparations, as well as to influenza vaccine antigens in renal transplant recipients.
Unlike cyclosporin, mycophenolate mofetil did not cause osteopenia or renal function decline in an in vivo rat model, but was associated with decreased levels of serum osteocalcin.
Prolongation of allograft survival with mycophenolate mofetil immunosup-pression has been demonstrated in a number of animal models. Established acute rejection episodes in rat cardiac and hindlimb allografts and canine renal allografts were completely reversed by mycophenolate mofetil treatment.
Pharmacological synergism between mycophenolate mofetil and tacrolimus has been observed in rat heart and porcine small bowel transplantation models, resulting in significantly prolonged graft survival compared with either drug alone.
Mycophenolate mofetil is rapidly and completely converted to the active metabolite MPA after oral administration; the parent drug is not detected in plasma. The mean oral bioavailability of MPA was estimated to be 94%. 24-hour area under the concentration-time curves (AUCs) for MPA were proportional to mycophenolate mofetil dose over the range 100mg to 3 g/day in renal transplant recipients. The probability of biopsy-proven graft rejection was significantly correlated with MPA AUC (p < 0.0001) and maximum plasma MPA concentration (Cmax) [p = 0.0008], but not with mycophenolate mofetil dose, in a randomised, double-blind concentration-controlled study of mycophenolate mofetil in 156 renal transplant recipients. Plasma MPA concentrations tend to increase with time (i.e. lower in the immediate post-transplantation period than in stable transplant recipients), but may decline again during the course of long-term therapy (>2 years).
MPA is metabolised to MPA glucuronide (MPAG) in the liver. MPAG is pharmacologically inactive and is excreted predominantly via the kidneys. MPAG is secreted in bile but glucuronidases from gut bacteria convert it back to MPA which is reabsorbed and recirculated. The apparent elimination half-life of MPA after a single oral dose of mycophenolate mofetil is approximately 18 hours.
Studies in kidney transplant recipients with impaired renal function have shown that the plasma MPA profile is not significantly affected by haemodialysis or peritoneal dialysis or worsening renal dysfunction, but that MPAG accumulates and MPA free fraction increases as renal function deteriorates.
MPA AUCs tended to be lower in paediatric patients than in adults when doses were adjusted by bodyweight. Dose adjustments based on body surface area in children yielded AUCs closer to the adult values.
Coadministration of mycophenolate mofetil did not significantly affect the pharmacokinetics of either cyclosporin or tacrolimus in single- and/or multiple-dose studies in renal transplant recipients. However, coadministration of cyclosporin reduced trough MPA concentrations in renal transplant recipients receiving mycophenolate mofetil and prednisone compared with those in patients receiving the latter drugs with no cyclosporin. MPA plasma profile was significantly enhanced, and MPAG concentrations were significantly reduced, in mycophenolate mofetil recipients also receiving tacrolimus compared with those in patients also receiving cyclosporin.
Mycophenolate mofetil has been evaluated as part of a maintenance immunosup-pressive therapy regimen for the prevention of acute allograft rejection in renal, cardiac, liver, lung and pancreas transplant recipients. Its efficacy in treating established acute and chronic rejection of various organ allografts has also been assessed.
Mycophenolate mofetil was shown to have a sparing effect on the use of other immunosuppressives (e.g. cyclosporin, corticosteroids, tacrolimus) in various scenarios. A trend toward improvement of renal function has been observed after addition of mycophenolate mofetil and concomitant reduction or elimination of cyclosporin in patients with chronic cyclosporin nephrotoxicity. Likewise, the use of corticosteroids in maintenance therapy can be reduced or avoided in some patients receiving mycophenolate mofetil and cyclosporin, although the risk of rejection is increased in some cases of complete steroid withdrawal. Reduction of corticosteroid use may be of particular benefit in paediatric patients who are at risk of growth retardation due to steroid treatment.
Renal Transplantation: Three randomised, double-blind, multicentre trials involving nearly 1500 adult patients have shown that mycophenolate mofetil 2 or 3 g/day in conjunction with cyclosporin and corticosteroids caused significant reductions in the incidence of biopsy-proven acute rejection or treatment failure compared with azathioprine in the first 6 months after renal transplantation. Biopsy-proven rejection was reduced by approximately 50% in patients receiving mycophenolate mofetil compared with those receiving azathioprine, and by up to 70% compared with those receiving placebo. The rejection episodes experienced by mycophenolate mofetil recipients tended to be less severe than those of azathioprine or placebo recipients. The relative risk of graft loss due to rejection was reduced by approximately 60% for recipients of 2 g/day mycophenolate mofetil compared with control groups in a pooled analysis of the studies at one year. Overall, mycophenolate mofetil 2 g/day was considered to provide a better risk: benefit ratio than the 3 g/day dosage. Although the studies were not powered to detect a significant difference in long-term graft and patient survival, 3-year data show a trend toward improved outcomes with mycophenolate mofetil compared with azathioprine or placebo.
Combination regimens including tacrolimus and mycophenolate mofetil have also shown some efficacy in preventing acute rejection.
Mycophenolate mofetil was a significantly more effective rescue therapy than azathioprine, reversing early acute renal allograft rejection episodes and reducing the use of antilymphocyte agents for persistent rejection. Patients treated with mycophenolate mofetil for rejection were less likely to experience subsequent treatment failure (including further rejection, graft loss or death) than those treated with azathioprine. Mycophenolate mofetil was superior to high dose intravenous corticosteroid treatment in reversing persistent and/or refractory rejection, and in a meta-analysis, was equivalent to tacrolimus in improving renal function and lowering the incidence of graft loss, death, or other treatment failures in patients with refractory rejection. Chronic rejection was not completely reversible with mycophenolate mofetil, although stabilisation or improvement of renal function was observed in some patients.
High risk renal transplant recipients including African Americans and patients with delayed graft function may benefit from mycophenolate mofetil treatment, although African Americans appear to require a higher dosage (3 g/day) than Caucasians (2 g/day) to achieve similar therapeutic efficacy. Mycophenolate mofetil was effective in patients with delayed graft function, improving what would otherwise be a relatively poor prognosis for long term graft survival.
Cardiac Transplantation: A large double-blind, multicentre randomised, controlled trial has shown greater efficacy with mycophenolate mofetil 3 g/day than with azathioprine 1.5 mg/kg/day as primary therapy for prevention of rejection in 578 evaluable cardiac transplant recipients.
The primary end-point (biopsy-proven rejection with haemodynamic compromise or retransplantation or death at 6 months) occurred inll.4% of mycophenolate mofetil recipients versus 17.3% of azathioprine recipients (p = 0.045). Overall patient mortality and the proportion of deaths due to rejection at 1 year were lower in the mycophenolate mofetil group. At 3 years, mycophenolate mofetil recipients had significantly better graft survival that did azathioprine recipients (88.1 vs 81.6%, p = 0.029).
Mycophenolate mofetil 2 g/day was more effective than azathioprine (dosage not stated) in prevention of vascular constriction and progression of graft vascular disease, a manifestation of chronic rejection, in a randomised study in 20 cardiac transplant patients.
Treatment of recurrent cardiac allograft rejection with mycophenolate mofetil 3 to 3.5 g/day resulted in improvement of mean biopsy scores in several small studies. The frequency of recurrent rejections declined significantly after initiation of mycophenolate mofetil treatment, allowing for reductions in maintenance dosages of corticosteroids.
Liver Transplantation: Mycophenolate mofetil has not been used extensively in orthotopic liver transplantation, and to date no randomised study has demonstrated statistically significant benefit in terms of prevention of rejection. Several studies, however, have shown a trend toward reduced incidence of rejection when mycophenolate mofetil is added to cyclosporin- or tacrolimus-based therapy, and improved outcomes using mycophenolate mofetil for the treatment of established acute rejection episodes compared with corticosteroids.
The combination of mycophenolate mofetil and tacrolimus was more effective in preventing acute rejection than cyclosporin-based immunosuppression with or without mycophenolate mofetil.
Mycophenolate mofetil was effective as rescue therapy for acute liver allograft rejection episodes that had been refractory to treatment with corticosteroids and antilymphocytic agents in a small patient cohort; subsequent studies support this finding.
Lung Transplantation: Significantly fewer acute rejection episodes were experienced by patients receiving mycophenolate mofetil than those receiving azathioprine in small, nonrandomised studies in lung transplant recipients. Lung function was maintained more effectively with mycophenolate mofetil than with azathioprine, reflected in a trend toward a lower prevalence of obliterative bronchiolitis. This manifestation of chronic lung allograft rejection was controlled by treatment with mycophenolate mofetil in a small patient group.
Pancreas or Simultaneous Kidney/Pancreas Transplantation: Although larger, randomised trials are needed, a trend towards improved outcomes for preventing pancreas and simultaneous kidney/pancreas graft rejection and improving graft survival with mycophenolate mofetil treatment is evident from most, but not all, of the currently available data.
The main adverse effects associated with oral mycophenolate mofetil are GI events, haematological toxicity (especially leucocytopenia) and an increased incidence of some types of infections. Lower dosages (2 g/day) are generally better tolerated than higher dosages (3 g/day). Evaluation of the tolerability profile of mycophenolate mofetil is complicated by the fact that in all clinical trials patients have been treated with corticosteroids and cyclosporin in addition to the study treatment (mycophenolate mofetil, azathioprine or placebo).
Mycophenolate mofetil has been consistently reported to cause more GI adverse effects than azathioprine. In a long term double-blind trial in 578 patients undergoing cardiac transplantation, the incidence of diarrhoea at 6 months was 45% in those who received mycophenolate mofetil 3 g/day versus 34% in those who received azathioprine 1.5 to 3 mg/kg/day (p = 0.008). GI adverse effects associated with mycophenolate mofetil 3 g/day generally resolve when the drug dosage is reduced.
Leucocytopenia developed in 19% of patients receiving mycophenolate mofetil 2 g/day, 30 to 35% of patients receiving mycophenolate mofetil 3 g/day and 30 to 39% of patients receiving azathioprine in major clinical trials. The relative effect of mycophenolate mofetil and azathioprine on leucocytopenia may depend on dosage.
As with other immunosuppressive therapies, treatment with mycophenolate mofetil can be associated with opportunistic infections. Viral infections, including cytomegalovirus tissue-invasive disease, tended to occur more frequently with mycophenolate mofetil 3 g/day than with placebo or azathioprine in clinical trials. This possibly indicates over-immunosuppression with the regimens used, and fewer infections may occur if the dosages of cyclosporin and prednisone are reduced. Fatal infection or sepsis occurred in <2% of patients treated with mycophenolate mofetil.
Although the risk of lymphoma and other malignancies is increased in patients receiving immunosuppressive therapy, the incidence of malignancy did not appear to be significantly higher in patients treated with mycophenolate mofetil than those treated with placebo in a long term double-blind trial in 491 patients undergoing renal transplantation. Data are equivocal regarding the relative incidence of malignancy with mycophenolate mofetil versus azathioprine. The overall incidence of lymphoproliferative disease or lymphoma was approximately 1% in mycophenolate mofetil recipients in major clinical trials.
Mycophenolate mofetil carries a high acquisition cost relative to azathioprine, the drug it generally replaces in immunosuppressive therapy regimens. However, when other direct costs of treatment of organ transplant patients are considered, the use of mycophenolate mofetil appears to be a cost-effective alternative, for at least the first post-transplant year.
US and Swiss pharmacoeconomic analyses of mycophenolate mofetil use in renal allograft recipients concluded that mycophenolate mofetil offered both a therapeutic and a financial advantage over azathioprine in the early period following transplantation. Cost savings were primarily due to a reduction in hospitalisations and treatment expenditures associated with acute rejection episodes, which offset the higher drug acquisition cost. The cost effectiveness of mycophenolate mofetil immunosuppression over azathioprine was shown to be maintained over 3 years of treatment in one US model.
A 10-year model indicated that the acquisition cost of the drug may limit its cost effectiveness for long term treatment, but selective use in high-risk patients could be a viable option.
Preliminary results from a Japanese study suggest that mycophenolate mofetil is more cost effective than muromonab CD3 for treating refractory renal allograft rejection.
Dosage and Administration
Mycophenolate mofetil, in combination with cyclosporin and corticosteroids, is indicated for the prophylaxis of organ rejection in renal or cardiac transplant recipients. The recommended dose for renal transplant recipients is 1g twice daily, and for cardiac transplant recipients is 1.5g twice daily, starting as soon as possible after transplantation. Patients who are unable to tolerate oral medication can receive an intravenous formulation for up to 14 days, but should be changed to oral medication as soon as possible.
Careful observation of renal or cardiac transplant recipients with impaired renal function is recommended. Patients with chronic severe renal dysfunction should not receive more than lg twice daily of mycophenolate mofetil.
Caution is required in the use of mycophenolate mofetil in patients with active serious GI disease.
Complete white blood cell counts should be conducted regularly. If neutropenia develops (absolute neutrophil count <1.3 × 103/μl), administration of mycophenolate mofetil should be interrupted or the dosage reduced.
Mycophenolate mofetil should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. In women of childbearing potential, effective contraception must be used before, during and for 6 weeks after treatment. The manufacturers do not recommend breastfeeding during mycophenolate mofetil therapy.
Concomitant administration of mycophenolate mofetil with drugs that undergo renal tubular secretion or interfere with enterohepatic recirculation should be approached cautiously or avoided. Antacids containing magnesium or aluminium hydroxide should not be administered simultaneously with mycophenolate mofetil.