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  • Mycophenolate mofetil or MMF (CellCept® by Roche) is the mofetil ester of mycophenolic acid (MPA), the active immunosupressant.
  • MMF is used in combination with a calcineurin inhibitor like tacrolimus or cyclosporine plus steroids.
  • MMF therapy is often initiated at the time of transplant, but it is sometimes added to the immunosuppresion regimen following the 1st episode of acute rejection However, it should be noted that MMF is primarily a prophylactic agent and it is not first-line treartment for ongoing rejection
  • MMF has now largely supplanted azathioprine (see Transplantation 1997; 63: 39-47).
  • MPA inhibits T and B cell proliferation by blocking the production of guanosine nucleotides required for DNA synthesis.
  • MPA also prevents the glycosylation of adhesion molecules that are involved in the attachment of lymphocytes to endothelium and potentially in leukocyte infiltration of an allograft during an immune response.
  • MPA is a selective, reversible non-competitive inhibitor of inosine monophosphate dehydrogenase (IMP-DH), which is a critical enzyme for the de-novo synthesis of guanosine nucleotides. The drug appears to have some degree of specifity for the IMP-DH isoform found in the lymphcytes (both T and B).
  • MPA inhbits the proliferation of lymphocytes, fibroblasts, endothelial cells, and arterial smooth muscle cells.
  • Although MPA may also inhibit the recruitment of leukocytes into sites of inflammation and graft rejection, it has no effect on the production or release of the cytokines (IL-1 and IL-2) associated with early T-cell signal transduction. Hence, it is not effective in the treatment of ongoing acute rejection.
  • Randomized clinical trials have demonstrated that MMF, when used with cyclosporine and steroids, reduces the frequency and severity of acute rejection episodes in kidney, heart, and liver transplants, improves patient and graft survival in heart allograft recipients and increases renal allograft survival at 3 years. It has also been effective in reversing acute and resistant rejection episodes in heart, kidney and liver recipients. The addition of MMF to the immunosuppressive regimen may allow dose reduction of the calcineurin inhibitor (CSA or tacrolimus), thereby reducing its toxic effects. By permitting reduction in CSA or tacrolimus doses, MMF may stabilize or improve renal graft function in patients with calcineurin-inhibitor-related nephrotoxicity or chronic allograft nephropathy.

 

Available As

  • Oral: 250-mg and 500-mg capsules, and as 200 mg/mLoral suspension.
    It may also be prepared extemporaneously as an oral suspension (100 mg /mL; in cherry syrup; pH = 6.0 - 6.7; stable for at least four months at room temperature)(see AJHP '98; 55:926-929).
  • Injectable: 500 mg vial to be reconstituted in 14 mL of D5W to yield about 15 mL containing 33.33 mg/mLof MMF.

 

Dose and Administration

  • Oral
    If necessary, the dose should be increased gradually (over a few days) to improve tolerability and avoid GI problems.Trice daily dosing may be more effective than twice daily dosing.
    Children: 600 mg /m2 per dose given po twice a day (q12h) or 400 mg /m2 per dose given po three times daily (q8h)..
    Adults: Increase gradually from 500 mg bid to 750 mg tid (maximum = 3 g per day)
    Reduce dose in the presence of severe renal impairment (CLcr<20 mL/min). Reduce dose or discontinue therapy in the presence of diarrhea or neutropenia
    The drug should be taken on empty stomach. Avoid antacids and cholestyramine (see interactions below).
  • Intravenous:
    If necessary, MMF may be administered intravenously. IV and PO doses are equal. Each 500-mg vial should be reconstituted with 14 mL D5W to yield about 15 mL of MMF solution (33.33 mg/mL). The dose should be further diluted in D5W to a final concentration of about 6 mg/mL. The solution should not be refrigerated and should be administred within 4 hrs of preparation. The dose should be infused over at least two hrs. The manufacturer does not specify the type of container to use for parenteral MMF.

 

Pharmacokinetics

  • After its absorption, MMF is hydrolyzed by esterases (in plasma, liver, and kidney) to the active metabolite mycophenolic acid (MPA).
  • MPA undergoes conjugation (mainly in the liver) to the glucoronide (MPAG), a significant amount of which is secreted into the bile only to be recycled to the liver (enterhepatic recirculation) where it may be converted back to MPA. Thus, enterohepatic recirculation is thought to contribute significantly to the MPA serum level. However, most of MPAG is eliminated in the urine via tubular secretion and its clearance correlates well with GFR [CL (L/hr) = 0.026 GFR (mL/min) - 0.13].
  • Most of the drug is ultimately excreted in the urine mostly by secretion via the organic anion transport system in the proximal tubule. A small fraction (~5%) is eliminated in the feces.
  • Neither MPA nor MPAG is removed by conventional hemodialysis to any significant extent.
  • Oral bioavailability (of MPA) varies from about 95% in heathy volunteers to about 50% in newly transplanted patients
  • Volume of distribution of MPA = 4 L/kg
  • Protein binding of MPA = 97 % and that of MPAG = 82%
  • Time to Cmax= 1.5 hrs;    Elimination half-life is about18 hrs

 

Contraindications and Warnings

  • Allergic reactions to MMF have been observed; therefore, it is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. IV MMF is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).
  • IV MMF solution should never be administered by rapid or bolus IV injection.
  • Increased susceptibility to infections.
  • Increased risk of lymphoproliferative disorders (e.g., lymphoma)
  • Increased risk of GI bleed (occurs in ~3% of patients).
  • Dose should be decreased in patients with severe renal impairment.
  • Exercise extreme caustion when MPA is used in patients with childbearing potential and in lactating mothers (MPA is transferred into the mother's milk)
  • The safety of using MPA in children has not been established yet.
  • Pregnancy category C: This drug should be used only if the potential benefits justify potential risk to the fetus.

 

Main Side Effects

  • Abdominal pain, diarrhea, constipation, and nausea/vomiting.
    Peripheral edema; hematuria; acne; dyspnea and cough
  • Drug-induced fever (~20% of patients).
  • Infections:
    • Bacterial, (wound; pneumonia; UTI; etc)
    • Viral (e.g., CMV)
    • Fungal (e.g., candida)
  • Headache, back pain, chest pain, insomnia, dizziness, and tremor.
  • Anemia, leukopenia, thrombocytopenia, leukocytosis.

 

Drug Interactions

  • Antacids and oral Mg supplements markedly reduce MMF absorption - separate by 2 -3 hours
  • Cholestyramine binds MPAG in the intestine interrupting the enterohepatic reciruclation of the drug. This interaction leads to a marked (up to 50%) reduction in MPA bioavailability
  • The plasma level of drugs that are substrates of the proximal tubule organic transport system (e.g., acyclovir and ganciclovir) may increase in the presence of MPAG due to competition for tubular secretion (this interaction may be significant in patients with markedly reduced renal function). Similarly, probenecid may increase the level of mycophenolate due to inhibition of tubular secretion.
  • The bioavailability (AUC) and the trough level of mycophenolate are significantly higher when MMF is used as part of a tacrolimus-based regimen than when used in combination with cyclosporine [Zucker '97]. Tacrolimus inhibits the glucuronidation (and elimination) of MPA [Zucker '99].
  • The administration of antibiotics such as metronidazole and fluoroquinolones and the resultant elimination of intestinal flora are associated with a 35-45% reduction in MPA bioavailability (AUC) [Naderer '99]. An adjustment in MMF dose may be required when these antibiotics are given to transplant patients
  • Note that unlike the case of azathioprine (Imuran), there is no basis for any pharmacokinetic interaction between MMF and allopurinol.
  • Salicylates, in high doses, may increase the free fraction of MPA

 

References

  1. CellCept® Prescribing Information
  2. Rose ML et al. Mycophenolate mofetil decreases antibody production after cardiac transplantation. J Heart Lung Transplant. 2002;21(2):282-5.
  3. Kaufman DB et al. A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation: comparison of two maintenance immunosuppression protocols: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus. Transplantation. 2002;73(2):169-77.
  4. Kreis H. New strategies to reduce nephrotoxicity. Transplantation. 2001;72(12 Suppl):S99-104.
  5. Chan L. et al. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am J Kidney Dis. 2001;38 (Suppl 6):S2-9.
  6. Mele TS et al. Immunopharmacology. 2000;47(2-3):215-45.
  7. Bullingham et al. Clinical Pharmacokinetics '98; 34(6)429-455
  8. Zucher et al. Therapeutic Drug Monitoring '99; 5(3):225-32

 

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