Idiopathic Pulmonary Fibrosis (IPF)


CellCept® (mycophenolate mofetil) is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in individuals that have undergone kidney, heart, or liver transplantation. CellCept should be used in combination with other immunosuppressants.1

Although it is approved for use in children and adults who have had kidney transplants, the safety of CellCept in children who have had a heart transplant is unknown. CellCept is administered twice a day and is formulated as 250 mg capsules, 500 mg tablets, a powder for reconstitution and administration as an oral suspension (200 mg/mL), or a single-dose vial of 500 mg for injection after reconstitution for patients that do not tolerate oral medication.1 

The active pharmaceutical ingredient of CellCept is mycophenolate mofetil (MMF), which is the first-line drug prescribed for patients who have undergone solid organ transplantation.2 Common adverse reactions with MMF treatment include gastrointestinal issues (diarrhea and vomiting), leukopenia, and an increased frequency of opportunistic infections. The use of MMF is also associated with teratogenic effects in humans, with an increased risk of developing cancers such as lymphoma and skin malignancies. This effect appears to be linked to the duration of treatment and its intensity.1

CellCept
Credit: Getty images

Pharmacodynamics of Mycophenolate Mofetil

MMF is a prodrug of mycophenolic acid (MPA) (2-morpholinoethyl ester) that is able to block lymphocyte proliferation by potently and selectively inhibiting inosine monophosphate dehydrogenase (MPDH) and therefore, the de novo purine biosynthesis in T and B lymphocytes.1,3 By inhibiting the proliferation of lymphocytes, MMF leads to the suppression of the cell-mediated immune response and the suppression of antibody formation.3 MMF treatment also provides an anti-inflammatory effect and inhibits the recruitment of leukocytes into sites of inflammation.1

The potent immunosuppressive activity of MMF is used for reducing rejection of transplanted organs, including the lungs, and in the treatment of chronic rejection in lung transplantation. It is also used for rheumatoid arthritis and sarcoidosis.3 

MMF is rapidly and completely absorbed. MPA is further glucuronidated to phenolic glucuronide (MPAG), which is not pharmacologically active and is mostly eliminated in the urine. MPAG can be converted to MPA during enterohepatic recirculation, however. MPA and MPAG are about 97% and 82% bound to albumin, respectively.1,4

Different drug interactions have been described for patients during treatment with MMF. Antacids with magnesium or aluminum hydroxide, proton pump inhibitors (PPIs), and antibiotics are a few examples of drugs that potentially interfere with MMF administration and need additional monitoring.1

Get detailed prescribing information on the CellCept monograph page at MPR.

Mycophenolate Mofetil in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive lung fibrosis. This disease has a very poor prognosis, with a median survival of less than 5 years after diagnosis.3,5 The only hypothetical cure for patients with IPF is a lung transplant, however, not all patients will be candidates for this surgical procedure. The median survival after lung transplantation is 5 years.3

The pharmacological treatment of IPF previously relied on combinations of corticosteroids, immunosuppressants (azathioprine or cyclophosphamide), and antioxidants (N-acetylcysteine). The development of severe adverse events and an increase in death rate led to a halt in the use of these drugs for addressing IPF. Currently, there are 2 approved antifibrotic therapies for treating IPF, pirfenidone and nintedanib. These drugs were shown to reduce the annual forced vital capacity (FVC) decline in patients with mild and moderate disease in different clinical trials.3

MMF use in different lung diseases has been expanding. This increased use is associated with evidence of antiproliferative and antifibrotic effects,6,7 differing from other immunosuppressive agents such as azathioprine. A small series study reported on the safety and tolerability of MMF in 125 patients that were under treatment for a median of 897 days. The report associates improvements in the FCV with stable or improved pulmonary physiology over a 2.5-year follow-up, suggesting that MMF is a promising therapy for pulmonary fibrosis.8 MMF has also been used in scleroderma and chronic pneumonia because the fibrotic histopathology underlying these diseases is similar to that of IPF.3

Evidence of the use of MMF in IPF and its clinical efficacy is scarce, however. A study that included 10 patients with IPF who were treated with MMF reported no increased benefits in radiologic and physiologic parameters after 6 and 12 months of treatment and no significant changes in FVC.5 The study did not report any significant adverse events such as infections or liver changes; however, it showed important limitations and a lack of correlation between drug effect and disease outcome.

A more recent study performed a retrospective multicohort analysis of patients with IPF who were treated with MMF, and it compared treated patients with individuals who were not treated or received treatments with no observed benefits. The analysis pointed to an increase in FVC stability and an improved trend in median overall survival in MMF-treated patients.3

References

1. CellCept®. Genentech USA, Inc. Accessed August 9, 2021.

2. van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int. 2015;28(5):508-515. doi:10.1111/tri.12554

3. Nambiar AM, Anzueto AR, Peters JI. Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis. PLoS One. 2017;12(4):e0176312. doi:10.1371/journal.pone.0176312

4. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998;34(6):429-455. doi:10.2165/00003088-199834060-00002

5.Tzouvelekis A, Bouros E, Oikonomou A, et al. Effect and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis. Pulm Med. 2011;2011:849035. doi:10.1155/2011/849035

6. Morath C, Schwenger V, Beimler J, et al. Antifibrotic actions of mycophenolic acid. Clin Transplant. 2006;20 Suppl 17:25-29. doi:10.1111/j.1399-0012.2006.00597.x

7. Petrova DT, Brandhorst G, Brehmer F, Gross O, Oellerich M, Armstrong VW. Mycophenolic acid displays IMPDH-dependent and IMPDH-independent effects on renal fibroblast proliferation and function. Ther Drug Monit. 2010;32(4):405-412. doi:10.1097/FTD.0b013e3181e44260

8. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40(5):640-646. doi:10.3899/jrheum.121043

Reviewed by Harshi Dhingra, MD, on 8/12/2021.