Mycophenolic acid

Mycophenolic acid

Mycophenolic acid (INN) or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It was initially marketed as the prodrug mycophenolate mofetil (abbreviated MMF) to improve oral bioavailability. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche) and Myfortic (mycophenolate sodium; Novartis).

Pharmacokinetics/pharmacology

Mycophenolate is derived from the fungus Penicillium stoloniferum. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.

Mycophenolate is potent and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three compound regimen of immunosuppressants, also including a calcineurin inhibitor (cyclosporin or tacrolimus) and prednisolone.

Clinical use

Indications

In general, mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant rejection in children >2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, and/or lung transplants in children >2 years.

An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in immune-mediated disorders including immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.

Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy. Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects. Walsh et al. even propose that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in patients without renal dysfunction, suggesting that mycophenolate will be encountered more frequently in medical practice.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhea, nausea, vomiting, infections, leukopenia, and/or anemia. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of patients) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.

"Novartis and FDA informed healthcare professionals and patients that use of mycophenolic acid (Myfortic Delayed- Release Tablets) during pregnancy is associated with increased risks of pregnancy loss and congenital malformations. The pregnancy category for Myfortic has been changed to Category D (Positive evidence of fetal risk). This change is a result of postmarketing data from the United States National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil (MMF) during pregnancy. MMF is converted to the active ingredient in Myfortic, following oral or intravenous administration.

"A patient who is planning a pregnancy should not use Myfortic unless she cannot be successfully treated with other immunosuppressant drugs. Healthcare professionals should discuss the risks and benefits of Myfortic as well as alternative immunosuppressant therapy with the patient. Female patients of childbearing potential must receive contraceptive counseling and must use effective contraception while taking Myfortic. Myfortic is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants, administered in combination with cyclosporine and corticosteroids".

The U.S. Food and Drug Administration (FDA) has added a list of warnings to the organ transplant drug stating that they can cause miscarriages and birth defects when used by pregnant women. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. The neurological condition known as progressive multifocal leukoencephalopathy attacks the brain and central nervous system and is usually fatal.

Comparison to other agents

Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. The exact role of mycophenolate vs azathioprine has yet to be conclusively established, but many centers use it in place of azathioprine for high-risk patients, or patients that have already experienced an episode of acute rejection. In long-term immunosuppression, it may be used to avoid calcineurin inhibitors or steroids.

Potential future uses

Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), and pemphigus vulgaris (PV) with success for some patients.

It is also currently being used as a long-term therapy for maintaining remission of C-ANCA positive (Wegener's) granulomatosis. A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.

Footnotes

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