Mycophenolate Mofetil: Original Development and Primary Indication
Mycophenolate mofetil was developed as an immunosuppressive drug for the prophylaxis of organ rejection in solid organ transplantation, specifically for renal, cardiac, and hepatic transplants. 1
Historical Background and Discovery
Mycophenolate mofetil is a product of Penicillium fungi that was discovered in 1893 based upon its antibacterial properties, but since 1995 has been used primarily as an immunosuppressant drug to prevent rejection in solid-organ transplants. 2
The drug was specifically designed to inhibit inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo purine synthesis pathway of lymphocytes. 3
FDA-Approved Primary Indication
The FDA-approved indication for mycophenolate mofetil is for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants, used concomitantly with cyclosporine and corticosteroids. 1
The drug was licensed in 1995 for the prevention of acute renal allograft rejection in most countries following successful pivotal randomized double-blind multicentre trials involving nearly 1500 patients. 3
Mechanism Supporting Transplant Use
Mycophenolate mofetil is rapidly absorbed and hydrolyzed to form mycophenolic acid (MPA), which is a potent, selective, uncompetitive, and reversible inhibitor of IMPDH. 1
This inhibition blocks the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA, leading to selective lymphocyte suppression. 1
T- and B-lymphocytes are critically dependent on de novo synthesis of purines for their proliferation, whereas other cell types can utilize salvage pathways, giving MPA potent cytostatic effects specifically on lymphocytes. 1, 4
MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation, and suppresses antibody formation by B-lymphocytes. 1
Clinical Development Evidence
In large randomized controlled trials in renal and cardiac transplant recipients, mycophenolate mofetil demonstrated significant efficacy in reducing the incidence of acute rejection compared with azathioprine in the first year after transplantation. 5
After 6 months in pivotal trials, the rates of biopsy-proven rejection were significantly reduced in patients receiving MMF at dosages of 1 to 3 g/day when combined with cyclosporin and corticosteroids. 3
Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow). 1
Secondary Applications Developed Later
While the primary development was for transplant rejection prophylaxis, mycophenolate mofetil has subsequently been used to treat autoimmune disorders including:
- Systemic lupus erythematosus and immune thrombocytopenia 2
- Steroid-refractory acute graft-versus-host disease 2, 6
- Interstitial lung disease 7
- Psoriasis 6
These autoimmune applications represent off-label uses that emerged after the drug's initial development and approval for solid organ transplantation.