Mycophenolate …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.13.2021
Released 03.01.2004
Expires For CME 03.13.2024

Mycophenolate

Author: K K Jain MD†

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Mycophenolate

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Introduction

Historical note and terminology

Mycophenolate mofetil is the semisynthetic morpholinoethyl ester of mycophenolate acid, which has been developed as an immunosuppressive agent to prevent rejection of transplanted organs. It was commercialized as CellCept by Hoffmann-La Roche. Mycophenolic acid was originally used to treat psoriasis in the 1970s. More recently, this agent has been used to treat several inflammatory conditions, including systemic lupus erythematosus, particularly in lupus nephritis. Currently it is in clinical trials for autoimmune myasthenia gravis, which will be the focus of this article. However, the knowledge of clinical pharmacology and safety of this drug is based on use in transplant patients, the only approved use.

Pharmacology

Pharmacodynamics. Mycophenolate is a suppressor of T-cell proliferation and adhesion. Its primary mode of action is inhibition of inosine monophosphate dehydrogenase, a purine salvage pathway required by T lymphocytes. Moreover, mycophenolic acid is a 5-fold more potent inhibitor of the type II isoform of inosine monophosphate dehydrogenase, which is expressed in activated lymphocytes, than of the type I isoform of inosine monophosphate dehydrogenase, which is expressed in most cell types. Therefore, mycophenolic acid has a more potent cytostatic effect on lymphocytes than on other cell types. As the use of mycophenolate for indications other than organ transplantation is being explored, additional effects of the drug have been observed. Mycophenolate improves neuromuscular junction function in myasthenia gravis as demonstrated by single fiber EMG and is considered a useful biomarker of early response in clinical trials.

Pharmacokinetics. Following oral administration, mycophenolate mofetil is rapidly and completely absorbed and is rapidly converted to its active form, mycophenolic acid, on reaching the systemic circulation. Systemic plasma clearance of intravenous mycophenolate mofetil is approximately 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fall below the measurable level within 10 minutes of the cessation of infusion. Mycophenolate is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide, by glucuronyl transferases in the liver and possibly elsewhere, which is then excreted by the kidney. Mycophenolate is extensively and avidly bound to serum albumin.

Pharmacogenetics. Elimination of mycophenolate mofetil in patients varies according to UGT1A8 gene polymorphisms, which can affect the activity of UDP-glucuronosyltransferase, the key metabolic enzyme for this drug (32).

Clinical trials

In an open-label study of 12 patients with refractory myasthenia gravis, 8 patients improved following treatment with mycophenolate without major side effects (04). A retrospective analysis of the use of mycophenolate in 85 patients with autoimmune myasthenia gravis has been carried out (16). Improvement was seen in 73% of patients as was assessed by the Myasthenia Gravis Foundation of America postintervention status. A subsequent double-blind, placebo-controlled study showed that mycophenolate treatment was effective in autoimmune myasthenia gravis (17). Limited evidence from Cochrane Database Systematic Review based on a few available randomized clinical trials showed no significant benefit from mycophenolate mofetil as monotherapy or with either corticosteroids or ciclosporin (10). Better designed trials of longer duration are needed.

Retrospective analysis of data from 102 patients with AChR-antibody-positive myasthenia gravis shows that mycophenolate starts to produce improvement after 6 months, both in combination with prednisone and as monotherapy (11).

An ongoing prospective, multicenter observational cohort study is comparing the effectiveness of azathioprine and mycophenolate mofetil as treatments for myasthenia gravis with a patient-centered primary outcome measure to guide clinicians, patients, and payers regarding the choice of treatment options (ClinicalTrials.gov identifier: NCT03490539). The study started in 2018 and expected completion date is November 2020.

An ongoing observational cohort trial in the real-world clinical setting is recruiting new-onset ocular myasthenia patients in different regions of China with treatment choice between steroids, azathioprine, tacrolimus, and mycophenolate mofetil (ClinicalTrials.gov identifier: NCT04182984). Patients are followed up prospectively on regular to assess the outcomes of treatments and monitor any side effects. The study started in December 2019 and estimated completion date is November 2024.

Indications

Mycophenolate is approved for prevention of rejection in patients receiving heart, kidney, and liver transplants.

Off-label uses

	• According to the Myasthenia Gravis Foundation of America patient registry, 24% of the patients have been treated with mycophenolate (05).
	• A randomized study demonstrated no benefit of mycophenolate 20 mg/day with prednisone compared to 20 mg/day of prednisone alone after 12 weeks in patients with myasthenic weakness (20). A prospective, randomized, double-blind, placebo-controlled, phase III trial showed that mycophenolate treatment was not superior to placebo in maintaining myasthenia gravis control during a 36-week schedule of prednisone tapering (25).
	• Mycophenolate is an effective adjunctive therapy for the treatment of severe, refractory, and steroid-dependent myasthenia gravis.
	• Mycophenolate is used as a non-nephrotoxic alternative to cyclosporine in cyclosporine-dependent myasthenia gravis patients with renal impairment.
	• Case reports show promising results of mycophenolate in juvenile myasthenia gravis and chronic inflammatory demyelinating polyradiculoneuropathy of childhood, diseases in which adverse effects of chronic steroid therapy are a concern (15). Studies to examine its relative efficacy, tolerability, and adverse effects in children are needed.
	• Mycophenolate may have a role in treating ocular myasthenia gravis where steroids are contraindicated (09).
	• Inflammatory myopathies
	• Inflammatory neuropathies
	• Multiple sclerosis. Results of a retrospective multicenter study suggest that mycophenolate can improve or stabilize multiple sclerosis patients and can be used as an alternative therapy (18). In a small study, the evidence for efficacy of mycophenolate as add-on to interferon beta-1a in new-onset relapsing-remitting multiple sclerosis was insufficient (30).
	• Experimental allergic encephalomyelitis
	• Systemic lupus erythematosus. Although both mycophenolate and cyclosporin showed a significant effect on disease activity and circulating B-cell subsets in systemic lupus erythematosus in a comparative study, only myophenolate reduced circulating plasmablasts and plasma cells as well as circulating free light chains within 3 months of induction therapy (08). A systematic review of clinical trials indicates that the efficacy of mycophenolate in neuropsychiatric manifestations of systemic lupus erythematosus is unproven and should be limited to those patients who are refractory or intolerant to cyclophosphamide (19).
	• Mycophenolate mofetil, in combination with steroids, has been used successfully in a case of primary angiitis of the central nervous system (03).
	• Mycophenolate is associated with reduction in relapse frequency and reduced disability in patients with neuromyelitis optica (13).
	• Mycophenolate has been reported to produce improvement in one case of idiopathic hypertrophic pachymeningitis (02).
	• Behçet disease involving the nervous system (27).
	• Results of a comparative open clinical study on patients with systemic lupus erythematosus indicate that both cyclophosphamide and mycophenolate can regulate the lymphocyte subsets and consequent abnormal immunity, but mycophenolate produces fewer side-effects than cyclophosphamide (31).
	• A patient with chronic inflammatory demyelinating polyneuropathy who continued to deteriorate despite treatment with high-dose glucocorticoids was later diagnosed with a combination of chronic inflammatory demyelinating polyneuropathy and myasthenia gravis (24). He improved after treatment with pyridostigmine bromide, prednisone, and mycophenolate mofetil, raising the possibility of a common immunological abnormality in this rare association.
	• Mycophenolate does not affect disease progression but influences relapse rate in progressive multiple sclerosis (07).

Special considerations

Complete blood counts should be done weekly during the first month of treatment, twice monthly during the second and third months, and monthly thereafter during the first year.

Pediatric. Pharmacokinetics and efficacy of treatment of mycophenolate, as studied in transplant patients between the ages of 1 to 18 years, are like those of adults.

Geriatric. Use of mycophenolate has not been studies in geriatric patients.

Pregnancy. All immunosuppressant agents have potential adverse effects during pregnancy. Animal studies with mycophenolate have shown teratogenic effect. A study from a group of different European teratogen information services has provided evidence of a specific mycophenolate embryopathy with patterns that include external ear anomalies ranging from hypoplastic pinna to complete absence of pinna, cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia (23). There are no adequate or well-controlled studies of the mycophenolate therapy during pregnancy, and its use is not recommended unless the benefits of treatment outweigh the risks. Contraception is used during mycophenolate treatment in women of child-bearing age. Women on mycophenolate therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least 6 weeks before becoming pregnant.

Anesthesia. No interaction of mycophenolate has been reported with anesthetic agents.

Renal insufficiency decreases the protein binding of mycophenolate and increases free mycophenolic acid concentrations. The disposition of mycophenolic acid in patients with severe renal impairment may be significantly affected by this change in protein binding.

Adverse effects

Enteric-coated mycophenolate sodium was developed to reduce the upper-gastrointestinal adverse effects by releasing mycophenolate in the small intestine rather than the stomach, but this anticipated improvement of upper gastrointestinal side effects has not been achieved in practice.

Serious adverse effects with mycophenolate are fewer compared to the older immunosuppressive agents. Product warning states the risk of developing lymphoma and gastrointestinal infections. Neutropenia is also a major concern. Opportunistic infections may be associated with increased immune suppression.

There is a report of a patient who developed urticaria during treatment of systemic lupus erythematosus with mycophenolate, and the diagnosis was confirmed by recurrence of urticaria on rechallenge (28). A desensitization protocol successfully induced tolerance to mycophenolate.

A patient with myasthenia gravis was effectively managed with mycophenolate but developed CNS lymphoma after 3 years of treatment, but it regressed after withdrawal of mycophenolate (29). Another patient with myasthenia gravis on long-term mycophenolate mofetil and pyridostigmine presented with neurologic deterioration, and MRI showed appearance of multiple brain abscesses, but a stereotactic biopsy reported B-cell lymphoma (14).

Treatment with mycophenolate is recommended in centers equipped to care for transplant patients and the complications of this treatment.

Mycophenolate mofetil has been reported to induce progressive multifocal leukoencephalopathy in a kidney transplant patient who improved following discontinuation of the drug (06).

Results of a retrospective cohort study suggests that discontinuation/marked reduction of mycophenolate therapy may increase the risk of myasthenia gravis exacerbation many fold (21).

A patient with myasthenia gravis who developed cytomegaloviral retinitis due to immunosuppression as a result of mycophenolate treatment was treated successfully with intravitreal injection of ganciclovir and foscarnet as well as oral valganciclovir (22).

References

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02: Assiotis A, Hadjivassiliou M. Idiopathic hypertrophic pachymeningitis responsive to mycophenolate. Acta Neurol Belg 2011;111(3):252-4. PMID 22141296
03: Chenevier F, Renoux C, Marignier R, et al. Primary angiitis of the central nervous system: response to mycophenolate mofetil. J Neurol Neurosurg Psychiatry 2009;80(10):1159-61. PMID 19762907
04: Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 2001;56(1):97-9. PMID 11148243
05: Cutter G, Xin H, Aban I, et al. Cross-sectional analysis of the Myasthenia Gravis Patient Registry: disability and treatment. Muscle Nerve 2019;60(6):707-15. PMID 31487038
06: El Kabbaj D, Hassani M, Kadiri M, et al. Mycophenolate mofetil associated with progressive multifocal leukoencephalopathy with successful outcome. Saudi J Kidney Dis Transpl 2012;23(4):790-3. PMID 22805393
07: Fakih R, Matiello M, Chitnis T, Stankiewicz JM. Efficacy and safety of mycophenolate mofetil in progressive multiple sclerosis patients. J Neurol 2018;265(11):2688-94. PMID 30203314
08: Fassbinder T, Saunders U, Mickholz E, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther 2015;17:92. PMID 25890338
09: Haines SR, Thurtell MJ. Treatment of ocular myasthenia gravis. Curr Treat Options Neurol 2012;14(1):103-12. PMID 22037997
10: Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev 2007;(4):CD005224. PMID 17943844
11: Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 2010;41(5):593-8. PMID 20405499
12: Hobson-Webb LD, Hehir M, Crum B, Visser A, Sanders D, Burns TM. Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis. Muscle Nerve 2015;52(2):211-5. PMID 25906756
13: Jacob A, Matiello M, Weinshenker BG, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 2009;66(9):1128-33. PMID 19752302
14: Liang S, Lim JX, Lee HY, Low SY. Primary central nervous system lymphoma presenting as multifocal brain abscesses. Cureus 2020;12(12):e12068. PMID 33489486
15: McMillan HJ, Darras BT, Kang PB. Autoimmune neuromuscular disorders in childhood. Curr Treat Options Neurol 2011;13(6):590-607. PMID 21912840
16: Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology 2003a;61(10):1438-40. PMID 14638974
17: Meriggioli MN, Rowin J, Richman JG, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann N Y Acad Sci 2003b;998:494-9. PMID 14592919
18: Michel L, Vukusic S, De Seze J, et al. Mycophenolate mofetil in multiple sclerosis: a multicentre retrospective study on 344 patients. J Neurol Neurosurg Psychiatry 2014;85(3):279-83.** PMID 23704316
19: Mok CC. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol 2007;36(5):329-37. PMID 17963161
20: Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008;71(6):394-9. PMID 18434639
21: Oskarsson B, Rocke DM, Dengel K, Richman DP. Myasthenia gravis exacerbation after discontinuing mycophenolate: a single-center cohort study. Neurology 2016;86(12):1159-63. PMID 26850977
22: Patel S, Robin A. Cytomegalovirus retinitis in a patient on long-term mycophenolate mofetil treatment for myasthenia gravis. J Ophthalmic Vis Res 2020;15(3):428-31. PMID 32864075
23: Perez-Aytes A, Marin-Reina P, Boso V, Ledo A, Carey JC, Vento M. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet 2017;60(1):16-21. PMID 27639443
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26: Sharma A, Jablonow A, Jamal N, et al. Retrospective analysis of Cellcept in generalized myasthenia gravis. Neurology 2017;88 (Supplement 16):P1.137.
27: Shugaiv E, Tüzün E, Mutlu M, Kiyat-Atamer A, Kurtuncu M, Akman-Demir G. Mycophenolate mofetil as a novel immunosuppressant in the treatment of neuro- Behçet's disease with parenchymal involvement: presentation of four cases. Clin Exp Rheumatol 2011;29(4 Suppl 67):S64-7. PMID 21968239
28: Szyper-Kravitz M, Sheinberg P, Sidi Y, Schiffenbauer Y, Trubniykov E, Shoenfeld Y. Hypersensitivity to mycophenolate mofetil in systemic lupus erythematosus: diagnostic measures and successful desensitization. Int Arch Allergy Immunol 2005;138(4):334-6. PMID 16224194
29: Vernino S, Salomao DR, Habermann TM, O'Neill BP. Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 2005;65(4):639-41. PMID 16116136
30: Xiao Y, Huang J, Luo H, Wang J. Mycophenolate mofetil for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev 2014;2:CD010242. PMID 24505016
31: Zhao L, Jiang Z, Jiang Y, Ma N, Wang K, Zhang Y. Changes in immune cell frequencies after cyclophosphamide or mycophenolate mofetil treatments in patients with systemic lupus erythematosus. Clin Rheumatol 2012;31(6):951-9. PMID 22349930
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Mycophenolate

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Mycophenolate

Mycophenolate …

Mycophenolate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Also in This Category

Anti-IgLON5 disease

Anti-LGI1 encephalitis

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Autoimmune autonomic neuropathy

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Myositis and cancer

Mycophenolate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Giant cell arteritis

Acupuncture

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

HTLV-1 associated myelopathy

Myositis and cancer

This is an article preview.
Start a Free Account
to access the full version.