What is Cellcept (mycophenolate mofetil)?

Mycophenolate Mofetil (CellCept): An Immunosuppressive Agent

Mycophenolate mofetil (CellCept) is a potent immunosuppressive medication that works by inhibiting lymphocyte proliferation through selective blockade of purine synthesis, primarily used in organ transplantation to prevent rejection and increasingly utilized in autoimmune conditions. 1, 2

Mechanism of Action

Mycophenolate mofetil (MMF) is a prodrug that is rapidly converted in the body to its active form, mycophenolic acid (MPA). Its immunosuppressive effects work through several key mechanisms:

• Primary mechanism: Selectively inhibits inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo purine synthesis 2
• Preferentially affects T and B lymphocytes, which are more dependent on this pathway than other cell types 1
• Five times more potent against the type II isoform of IMPDH (expressed in activated lymphocytes) than the type I isoform (found in most other cells) 2
• Additional effects include:
  • Inducing apoptosis of activated T-lymphocytes
  • Suppressing glycosylation and expression of adhesion molecules
  • Reducing nitric oxide production by depleting tetrahydrobiopterin, a cofactor for inducible nitric oxide synthase 2

Clinical Applications

MMF is primarily used in:

1. Organ transplantation:

   • Prevents rejection in kidney, heart, and liver transplants 1
   • Used in combination with calcineurin inhibitors (cyclosporine or tacrolimus) and corticosteroids 3
   • Has progressively become the most used antimetabolite agent, replacing azathioprine 3

2. Autoimmune conditions:

   • Used in various inflammatory and autoimmune conditions including psoriasis 3
   • Management of steroid-refractory immune-related adverse events from cancer immunotherapy 3

Dosing and Administration

• Typically administered orally twice daily (every 12 hours) 3
• Available as capsules (250 mg) and tablets (500 mg) 1
• Dosing is individualized based on clinical response and drug levels
• Enteric-coated formulation of mycophenolic acid (EC-MPS) has been developed to reduce gastrointestinal side effects 3

Side Effects and Adverse Reactions

MMF has several important side effects that require monitoring:

1. Gastrointestinal effects:

   • Most common adverse effects (up to 35% of patients)
   • Include diarrhea, nausea, vomiting, abdominal pain 3, 4
   • Often dose-related and respond to dose reduction 5

2. Hematologic effects:

   • Bone marrow suppression leading to leukopenia, anemia, and thrombocytopenia 4
   • Requires regular complete blood count monitoring 4

3. Increased infection risk:

   • Opportunistic infections
   • Viral infections (particularly CMV)
   • Progressive multifocal leukoencephalopathy (rare but serious) 4

4. Pregnancy risks:

   • FDA black box warning for use during pregnancy
   • Associated with increased risk of miscarriage (49%) and birth defects (23%) 3
   • Contraindicated in pregnancy; requires two reliable forms of contraception 3
   • Requires 12-week washout period before attempting pregnancy 3

5. Malignancy risk:

   • Increased risk of lymphoma and skin cancers with prolonged use 4

Monitoring Recommendations

• Regular complete blood count monitoring:
  • Weekly for first month
  • Twice monthly for second and third months
  • Monthly for remainder of first year
  • Every 1-3 months thereafter 4
• Liver function tests at least monthly 4
• Drug level monitoring if GI intolerance develops 4

Drug Interactions

Important drug interactions include:

• Drugs that may decrease MMF levels: antacids containing magnesium/aluminum, cholestyramine, rifampin 1
• Potential for increased toxicity when combined with other immunosuppressants 3
• Should not be used concurrently with azathioprine 1

Clinical Efficacy

MMF has demonstrated effectiveness in:

• Preventing acute rejection in organ transplantation 3, 6
• Allowing reduction of calcineurin inhibitor doses to improve renal function 3
• Treatment of steroid-refractory graft-versus-host disease with response rates of 31-48% 3

Important Considerations

• MMF is not generally potent enough to be used alone but is an important adjunct agent 3
• In liver transplantation, MMF has shown benefit in improving CNI-induced nephrotoxicity, blood pressure, and uric acid concentration 5
• Careful monitoring is essential due to the narrow therapeutic window and potential for serious adverse effects

MMF represents an important advance in transplant immunosuppression with demonstrated efficacy in preventing graft rejection when used as part of combination therapy.