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Mycophenolates
Questions
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Q16.1 How do MMF and mycophenolic acid (MPA) relate pharmacologically: (1) prodrug/active drug, or (2) active drug/active metabolite? (Pg. 178)
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Q16.2 What metabolic process is vital in maintaining MPA and mycophenolic acid glucuronide (MPAG) levels? (Pg. 179)
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Q16.3 Why are mycophenolate therapeutic benefits and adverse effects commonly localized to the skin and gastrointestinal tract? (Pg. 179)
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Q16.4 What clinical circumstances may cause an increase in bioavailable drug and/or active metabolites leading to a higher risk of infection and other toxicities? (Pg. 179)
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Q16.5 Concerning the MPA mechanism of action, (1) what purine biosynthesis enzyme is inhibited, and (2) why are activated lymphocytes specifically targeted by MPA? (Pg. 179)
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Q16.6 Which noncutaneous aspect of diffuse systemic sclerosis has demonstrated well-documented improvement with mycophenolate? (Pg. 182)
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Q16.7 What is the clinical advantage of enteric-coated mycophenolate (mycophenolate sodium)? (Pg. 182)
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Q16.8 What is the mycophenolate increased risk of (1) lymphoma in solid organ transplantation patients, and (2) nonmelanoma skin cancers in this population of patients? (Pg. 182)
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Q16.9 What is the most common category of adverse effects from mycophenolate and what are some specific examples in this category? (Pg. 183)
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Q16.10 What is the likelihood that mycophenolate truly induces progressive multifocal leukoencephalopathy (PML)? (Pg. 184)
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Q16.11 Why was a boxed warning added regarding pregnancy? (Pg. 184)
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Q16.12 Which antiviral medications can increase the toxicity of mycophenolate by inhibiting renal tubular excretion of MPA? (Pg. 185)
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Q16.13 What is the typical (1) starting dose for mycophenolate (mofetil and sodium formulations), and (2) therapeutically effective dose range for mycophenolate (mofetil and sodium formulations)? (Pg. 185)
Abbreviations used in this chapter
AE
Adverse effect/event
CBC
Complete blood count
Cr
Creatinine
CS
Corticosteroid(s)
CsA
Cyclosporine
EC-MPS
Enteric-coated mycophenolate sodium
IMPDH
Inosine monophosphate dehydrogenase
LFT
Liver function test
MMF
Mycophenolate mofetil
MPA
Mycophenolic acid
MPAG
Mycophenolic acid glucuronide
PASI
Psoriasis area and severity index
PML
Progressive multifocal leukoencephalopathy
PPD
Purified protein derivative
SCORAD
Severity Scoring of Atopic Dermatitis
SLE
Systemic lupus erythematosus
Introduction
Mycophenolate (mofetil and sodium) is an immunosuppressant with increasing usage in inflammatory skin conditions. Q16.1 It is a prodrug of the antimetabolite mycophenolic acid (MPA), and was originally isolated as a fermentation product of Penicillium stoloniferum in 1945. MPA was subsequently found to have antibacterial, antiviral, antifungal, antitumor, and immunosuppressive properties. In the 1970s, MPA was successfully used for the treatment of psoriasis. Because of concerns about carcinogenic potential, viral infections, and gastrointestinal (GI) adverse effects (AE), dermatologic trials with MPA were discontinued in 1977. Mycophenolate mofetil (MMF) was developed as a prodrug with greater bioavailability and tolerability. This form of mycophenolate is US Food and Drug Administration (FDA)-approved for the prevention of solid-organ transplant rejection. Increasingly, MMF has demonstrated long-term safety and tolerability. MMF has emerged as a significant part of the armamentarium of treatment for immunologic-mediated dermatologic diseases.
Pharmacology
Table 16.1 contains the key pharmacologic concepts for mycophenolate.
Table 16.1
Key Pharmacology Concepts—Mycophenolate Mofetil and Mycophenolate Sodium
| Drug Name | Absorption and bioavailability | Elimination | ||||
|---|---|---|---|---|---|---|
| Peak Levels (h) | Bioavailable (%) | Protein Binding (%) | Half-Life (h) (oral) | Metabolism | Excretion | |
| Mycophenolate mofetil | 1–1.5 | 80.7–94 | >97 (MPA bound to albumin) | 18 (MPA) | MPA (active metabolite), MPAG (not active) | Urine <1%, feces 6%, 87% in urine as MPAG |
| Enteric-coated mycophenolate sodium | 1.5–2.75 | 72 | Same | MPA: 8–16 MPAG: 13–17 |
Same | Urine 3%, feces; >60% in urine as MPAG |
MPA, Mycophenolic acid; MPAG, mycophenolic acid glucuronide.
Q16.2 MMF is the 2-morpholinoethyl ester of MPA. With oral administration, MMF is rapidly absorbed and then converted by esterases in the plasma, liver, and kidney to MPA, the active metabolite. MPA is inactivated in the liver via glucuronidation. The resulting inactive compound, a phenolic glucuronide of MPA (MPAG), is secreted into the bile and recycled to the liver by enterohepatic recirculation. This recirculation is vital for maintaining MPA/MPAG serum levels. MPAG remains inactive until it is converted back to MPA by the enzyme β-glucuronidase. Q16.3 High levels of β-glucuronidase are found primarily in the epidermis and GI tract, thus explaining both the efficacy of MMF in treating dermatologic disorders and the most common AE.
Drugs, disease states (such as diarrhea), and/or individual genetic variations that alter this pathway significantly affect MMF pharmacokinetics. For example, an in vitro study evaluated polymorphisms in the UDP-glucuronosyltransferase enzyme, UGT1A8 gene, and demonstrated mutations leading to rapid and poor metabolizers of MMF. Moreover, stem cell transplant recipient inosine monophosphate dehydrogenase 1 (IMPDH 1 ) genotypes may be a predictive biomarker to MMF that lower risk of chronic graft-versus-host disease. Despite well-defined optimal blood concentrations, an excellent clinical example of the importance of pharmacokinetics and pharmacogenomics lies in monitoring MMF in the setting of lupus erythematosus (LE). Drug-level monitoring may offer identification of nonadherence and overexposure, thus aiding in purposeful counseling and dose adjustment. In the future, clinicians may be able to test for these individual variations to help predict a patient’s expected response and risk of AE.
After dosing, the first peak in plasma levels occurs within the first hour. A second peak, the result of the enterohepatic recycling, occurs after 6 to 12 hours. Given the two peaks in drug levels, twice-daily dosing is recommended. The half-life of MPA is approximately 16 to 18 hours in healthy individuals. Over 90% of the administered dosage is excreted in the urine as MPAG. Renal impairment does not have a significant effect on MPA levels, the active metabolite; therefore, it is unlikely that dose reduction is necessary in these cases. Q16.4 As the majority of MPA and MPAG in the serum is bound to albumin, altered levels of this protein, as may occur in renal or liver disease, or concomitant use of medications that compete for albumin-binding sites, may necessitate a decrease in MMF dosing. Exposure to increased levels of unbound MPA may be a predictor of infections and hematologic toxicity. (See Drug Interactions section.)
Mechanisms of Action
The immunosuppressive effects of MMF are primarily related to its effects on purine biosynthesis. Q16.5 Two cellular mechanisms exist for purine nucleotide generation: the de novo pathway and the salvage pathway ( Fig. 16.1 ). Lymphocytes are unique in their complete dependence on the de novo pathway. MPA noncompetitively binds to and inhibits inosine monophosphate dehydrogenase (IMPDH), the key enzyme in the de novo pathway. In addition, MMF has a much higher affinity for the isoform IMPDH 2 of IMPDH that is expressed in activated lymphocytes. By selectively inhibiting the de novo pathway within activated lymphocytes, MMF is able to target those lymphocytes most responsible for disease while having a minimal effect on other organ systems and cell types. This broad therapeutic index is one of the key reasons for the increased use of MMF in various dermatologic diseases.
In addition to inhibiting purine biosynthesis, in vitro studies show that MMF can affect numerous other cellular processes implicated in disease. MMF reduces the recruitment and egress of inflammatory cells into areas of inflammation by altering the expression and processing of cell surface adhesion molecules, specifically reducing expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin. Dendritic cells, one of the primary antigen-processing cells of the skin, are negatively affected by MMF. MMF inhibits antibody production by activated B-cell lymphocytes. Finally, MMF has been shown to inhibit several fibroblast functions implicated in tissue fibrosis. Such diverse mechanisms of action likely explain the efficacy of MMF in a broad range of diseases.
Clinical Use
MMF has demonstrated effectiveness in the treatment of multiple inflammatory dermatologic diseases. These applications are currently off-label because of a lack of large randomized controlled trials. MMF is commonly used as a corticosteroid (CS)-sparing agent for patients who cannot tolerate other medications because of comorbidities, and also used for severe refractory disease that has failed other treatment regimens. Box 16.1 lists off-label dermatologic indications for the use of MMF.
Box 16.1
Mycophenolate Mofetil Indications
| US Food and Drug Administration-Approved Indications | |
| Renal, cardiac, and liver allograft rejection prevention | |
| Dermatologic Uses (all the following uses are off-label) | |
| Dermatitis & papulosquamous
Bullous dermatoses
Autoimmune connective tissue diseases
|
Vasculitis
Miscellaneous a
|
a Diseases not discussed in the text of this chapter.
Off-Label Dermatologic Uses
Psoriasis
In the 1970s, MPA demonstrated some effectiveness in the management of psoriasis. In one of the largest trials, 24 of 32 patients (75%) demonstrated 50% or greater improvement, with 41% achieving complete clearance at an average of 9.1 weeks. Although randomized double-blind placebo-controlled trials of MMF in psoriasis are lacking, several open trials have been published. The first series, published in 2000, described the treatment of eight patients on cyclosporine (CsA) who were switched to MMF 1 to 1.5 g twice daily. Overall response was poor, with either worsening disease or suboptimal control compared with prior treatment with CsA. Renal function did improve in six of six patients who had developed renal insufficiency from CsA. A prospective open-label study of 23 patients treated with 1 to 1.5 g twice daily demonstrated an average psoriasis area and severity index (PASI) reduction of 24% ( P < .001) at 6 weeks and 47% ( P < .001) overall at 12 weeks. Of note, 22% of patients did not respond. In 2009, a prospective multicenter open-label trial compared MMF and CsA head to head in 54 patients. Twelve-week PASI 75 scores for MMF and CsA were 18% and 58% respectively, demonstrating MMF inferiority to CsA in psoriasis. A randomized open trial of 38 patients compared methotrexate up to 20 mg weekly and MMF 2 g daily for 12 weeks. At 12 weeks, PASI had decreased by, respectively, 81% and 66% in the methotrexate and MMF groups. Both groups demonstrated significant improvement at 12 weeks and at 12-week follow-up, but there was no statistical difference between the groups.
MMF has also been reportedly used safely in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy. MMF may also have future use as a topical medication. MMF can be considered in some patients with recalcitrant psoriatic manifestations such as a generalized pustular flare.
The enteric-coated (EC) formulation of mycophenolate sodium (EC-MPS) was shown to be inefficacious as monotherapy for moderate to severe psoriasis in an open pilot study. The authors concluded that a dosage of this EC version of 720 mg twice daily could, however, be considered in the right setting in some patients with treatment resistant psoriasis. Clearly, MMF is a last-line treatment for psoriasis as there are a host of other therapies with more consistent effectiveness. However, given certain comorbidities or intolerance to other medications, MMF is another therapeutic option.
Immunobullous Disease
Pemphigus
Although MMF has been promoted as an effective CS-sparing agent in the treatment of pemphigus, until recently, randomized controlled trials were lacking. A randomized, placebo-controlled nonblinded study compared MMF (2 g daily) plus prednisone, MMF (3 g daily) plus prednisone, and placebo plus prednisone in 75 patients with pemphigus vulgaris. It did not demonstrate a significant difference in response rate at 52 weeks among the three groups. The patients on MMF (both doses), however, did show a more rapid and sustained response and received a lower cumulative prednisone dose. Milder disease in the placebo group may have contributed to a lack of difference in response among groups. In an open-label study of 42 patients with pemphigus vulgaris and pemphigus foliaceus on MMF, 64% achieved remission at a median of 9 months at an average dose of 35 to 45 mg/kg daily (thus 2450–3150 mg daily for a 70 kg adult). Several small studies have demonstrated efficacy of MMF both as monotherapy and as a CS-sparing agent in pemphigus. A meta-analysis also demonstrated that MMF was shown to decrease the number of disease relapses.
Few studies have directly compared MMF and other immunosuppressants in the treatment of pemphigus. A multicenter, nonblinded randomized clinical trial of 40 patients with pemphigus vulgaris and pemphigus foliaceus compared methylprednisolone plus azathioprine (2 mg/kg daily) and methylprednisolone plus MMF (2 g daily). Each group demonstrated similar efficacy, with more rapid onset of complete remission with azathioprine/methylprednisolone in 72% of patients at a mean of 74 days compared with 95% at a mean of 91 days in the MMF/methylprednisolone arm. Both had similar CS-sparing effects and AE, with no significant difference between the rate of infections, nausea, vomiting, and elevated liver function tests (LFT).
A randomized controlled open-label trial comparing (1) prednisolone, (2) prednisolone and azathioprine, (3) prednisolone and MMF, and (4) prednisolone and intravenous pulse cyclophosphamide for 1 year demonstrated no significant difference between groups in achieving complete remission or the rate of AE.
A case series has suggested efficacy and minimal AE profile to EC-MPS for the treatment for pemphigus vulgaris. Moreover, a retrospective study in 2012 suggested efficacy and safety for EC-MPS in both pemphigus vulgaris and pemphigus foliaceus, remarking that mycophenolate, either in MMF or EC-MPS formulation, was a first-line adjuvant treatment for pemphigus.
MMF is an excellent therapeutic choice for the treatment of pemphigus and appears to be an equally efficacious CS-sparing agent compared with other immunosuppressants.
Other Immunobullous Dermatoses
MMF has shown some efficacy in the treatment of bullous pemphigoid, predominantly in small series or case reports. The only randomized study to date was a multicenter, non–blinded comparison in 73 patients of azathioprine (2 mg/kg daily) plus methylprednisolone versus MMF (2 g daily) plus methylprednisolone. Remission was achieved in 92% of patients in the azathioprine group after a mean 23.8 days, versus 100% of patients on MMF after a mean 42 days, which was not statistically significant. Cumulative CS doses did not vary between groups. AE, including nausea, vomiting, and infections also did not differ between groups. Azathioprine, however, was associated with a significantly higher rate of elevated LFT. Success has also been reported in the treatment of cicatricial pemphigoid, paraneoplastic pemphigus, linear immunoglobulin A (IgA) bullous disease, linear IgA bullous disease of childhood, and epidermolysis bullosa acquisita.
Autoimmune Connective Tissue Disease
Lupus Erythematosus
Most studies on the use of MMF for LE focus predominantly on associated nephritis. Small numbers of case reports have demonstrated the efficacy of MMF in subacute cutaneous, discoid, and chilblain LE. In some of these cases, patients were also being treated with hydroxychloroquine. A large multicenter trial of 370 patients compared MMF with cyclophosphamide for the nonrenal aspects of lupus, including ‘mucocutaneous’ aspects of LE. It demonstrated that at 24 weeks, mucocutaneous lupus was improved to mild or nondetectable disease in 84% of patients on MMF versus 93% of patients on cyclophosphamide. The specifics of the skin manifestations in this study are unclear. A prospective open-label pilot study of 10 patients with subacute cutaneous LE (SCLE) resistant to standard therapy with topical CS, antimalarials, and azathioprine, demonstrated the efficacy of EC-MPS specifically with respect to cutaneous manifestations. To study improvement in skin lesions, they used the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 20-MHz ultrasound measurements to measure structure and thickness of skin lesions, and colorimetry to quantify the degree of lesional erythema. At a dose of 720 mg of EC-MPS twice daily, the CLASI score, thickness of lesions, and degree of erythema all improved to a statistically significant degree. All patients experienced improvement. Patients were treated for 3 months and had an additional 3-month follow-up period. Improvement in CLASI score was not seen before 1 month of treatment, and at the end of the 3 month follow-up period, three patients had a slight increase in CLASI, but the remainder sustained a stable CLASI score. One patient in their study had to dose reduce to 720 mg once daily secondary to diarrhea, and one had to come off therapy secondary to LFT elevation to three times the upper limit of normal. More studies concerning MMF are needed specifically addressing cutaneous LE.
Dermatomyositis
Few studies have evaluated the efficacy of MMF in the treatment of dermatomyositis. The largest to date is a retrospective study of 50 patients with juvenile dermatomyositis treated with MMF adjunctive therapy at 20 mg/kg (about 1.5 g daily in a 70-kg adult) divided twice daily. Patients had significant improvement of their cutaneous and muscular disease at 6 and 12 months. A large number of patients had infections during treatment, but none required hospitalization. Importantly, adjunctive MMF allowed a lower dosage of CS to be used. A retrospective chart review evaluated 12 patients with refractory dermatomyositis treated with MMF. Overall, 10 of 12 patients demonstrated improvement in their cutaneous and muscular disease with reduction in CS and/or other immunosuppressants, most by 4 to 8 weeks at a dose of 2 to 3 g daily. Other small series have described a CS-sparing benefit and improvement in muscular disease.
In addition to the cutaneous and muscular aspects of dermatomyositis, MMF shows promise in the treatment of the associated interstitial lung disease, even possibly in the more severe clinically amyopathic dermatomyositis associated with anti-MDA5 antibodies.
Vasculitis
MMF has demonstrated some efficacy in the treatment of various types of vasculitides, but most large studies and series focus on systemic organ vasculitis. Some studies have demonstrated efficacy in antineutrophil cytoplasmic antibody-associated vasculitides (including Wegener granulomatosis and microscopic polyangiitis), showing that MMF combined with prednisone is an alternative to cyclophosphamide for mild-moderate disease. These studies included patients with cutaneous vasculitis, but did not separate out the cutaneous response from that of other organ systems. Eosinophilic granulomatosis with polyangiitis, also known as Churg–Strauss disease, may also be responsive to MMF, as demonstrated in one case report. A multicenter randomized controlled trial showed MMF inferiority to azathioprine in maintaining disease remission following induction with cyclophosphamide and prednisolone in patients with Wegener granulomatosis and microscopic polyangiitis. Both treatments had similar AE rates. In a retrospective study of children with Henoch–Schönlein purpura, MMF was suggested to positively impact glomerular disease. Other case reports describe benefit in treating erythema elevatum diutinum (EED), recalcitrant cutaneous small-vessel vasculitis. nodular vasculitis, and hypocomplementemic urticarial vasculitis. MMF has shown mixed results in the treatment of Behçet syndrome.
Systemic Sclerosis
Q16.6 Several studies have demonstrated the efficacy of MMF in the treatment of interstitial lung disease associated with diffuse systemic sclerosis, and some consider it a first-line agent. Studies regarding treatment for cutaneous disease have been mixed, with recent studies more promising. The largest study to date evaluating skin disease in diffuse systemic sclerosis and MMF was an open-label cohort study evaluating multiple treatment regimens for diffuse systemic sclerosis (intravenous cyclophosphamide followed by MMF, antithymocyte globulin followed by MMF, MMF alone, no disease-modifying treatment, and other immunosuppressant treatments) in 147 patients. All groups had a reduction in skin score, but there was no statistical difference between treatment arms. In contrast, a large retrospective study comparing 109 patients with diffuse systemic sclerosis treated with MMF versus 63 patients treated with other immunosuppressants demonstrated a lower frequency of clinically significant pulmonary fibrosis and better 5-year survival from disease onset and commencement of therapy in the MMF-treated cohort. There was no significant difference between modified Rodnan skin scores and forced vital capacity between the various treatment regimens. An observational cohort study of 74 patients showed a modest statistically significant improvement in modified Rodnan skin scores. Additionally, a post hoc analysis from two randomized placebo controlled trials demonstrated statistically significant reductions in modified Rodnan skin scores with use of MMF and cyclophosphamide, with MMF better tolerated. Both the observational cohort and post hoc analyses highlight the importance of longer duration of therapy, with modified Rodnan skin scores primarily improving after at least 6 months of therapy. Clearly, randomized controlled trials are needed.
Atopic Dermatitis
A few small studies have shown MMF to be an additional therapeutic option for severe, refractory atopic dermatitis in adults. In a pilot open-label study of 10 patients treated for 12 weeks with MMF up to 2 g daily, patients had significant improvement and a reduction of 68% of the atopic dermatitis index Severity Scoring of Atopic Dermatitis (SCORAD). Long-term success for up to 29 months has also been seen in a few patients. Q16.7 A study of 10 patients with severe recalcitrant atopic dermatitis demonstrated efficacy and tolerability of the EC-MPS at a dosage of 720 mg twice daily for 6 months.
Contraindications
Absolute contraindications are pregnancy and drug allergy. Relative contraindications include lactation, peptic ulcer disease, renal disease, hepatic disease, cardiopulmonary disease, and drugs that interfere with enterohepatic recirculation, such as cholestyramine and certain systemic antibacterial agents. (See Drug Interaction section and Table 16.2 .)
Table 16.2
Drug Interactions—Mycophenolates
Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer, 2019. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ); Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management, 2019 Edition. Freeland, WA: H&H Publications, 2019. ( http://www.hanstenandhorn.com/ ).
| Drug Category | Drug Examples | Comments |
|---|---|---|
| Relatively High-Risk Drug Interactions a | ||
| NSAID | Various | Possible ↑ risk seizures |
| Narcotics | Various | Same |
| Immunosuppressants | Wide variety—relatively uncommon to have these SAE in dermatology | Biologics, JAK inhibitors, traditional (azathioprine, cyclosporine, etc.), chemotherapy, higher dose CS with risk of severe infections and/or myelosuppression |
| Vaccines | Live attenuated (Zostavax, others) | Immunize at least 2 weeks before mycophenolates; risk of (1) low/no immune response, (2) disseminated VZV (or other severe infections depending on vaccine) |
| Miscellaneous | Phenytoin, salicylates, xanthines | May compete with protein binding sites and ↑ MPA levels; effect may be transient |
| Antivirals | Acyclovir, ganciclovir, valganciclovir | Competes with MPA for renal tubular secretion, resultant ↑ MPA levels (especially with renal failure) |
| Miscellaneous | Probenicid | Same |
| Lower-Risk Drug Interactions | ||
| Bile acid sequestrants | Cholestyramine | May ↓ drug absorption with loss efficacy; give mycophenolate 2 h before/6 h after cholestyramine |
| Antacids | Aluminum, calcium, magnesium, H 2 antihistamines, proton pump inhibitors | Need gastric acid for cleavage to MPA; mineral based antacids also chelate the drug (chelation an issue with iron products) |
| Antibacterials | Various classes | May ↓ enterohepatic recirculation of MPA, with resultant ↓ drug levels; β-lactams, fluoroquinolones, TMP/SMX, clindamycin, linezolid, metronidazole |
| Antiretroviral agents | Nevirapine | Decreases serum levels MPA by unknown mechanism |
| Hormonal contraceptives | Levonorgestrel (as the progestin) | Same |
The dramatic increase in number of drug interactions in medicine requires some degree of selectivity in these tables (common usage, relative risk, focus on outpatient treatment).
CS, corticosteroid; JAK, janus kinase; MPA, mycophenolic acid; NSAID, nonsteroidal anti-inflammatory drug; SAE, serious adverse effect; SMX, sulfamethoxazole; TMP, trimethoprim; VZV, varicella-zoster virus.
a Overall highest-risk drug interactions indicated in bold italics .
Adverse Effects
MMF is generally well tolerated, with a preferred AE profile compared with other immunosuppressants. See Box 16.2 and the Drug Risks Profile Box 16.3 for a summary of AE, precautions, and warnings.
Box 16.2
Mycophenolate Mofetil Adverse Effects
Data from Genentech. Cellcept (mycophenolate mofetil) full prescribing information. Revised August 2018. www.gene.com/gene/products/information/cellcept . Accessed January 29, 2019.
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