10 Therapeutic dose monitoring of mycophenolate mofetil in dermatologic diseases (2).pdf

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Therapeutic dose monitoring of mycophenolatemofetil in dermatologic diseases

Olayemi Sokumbi, MD,a

Rokea A. el-Azhary, MD, PhD,a

and Loralie J. Langman, PhDb

Rochester, Minnesota

Background:Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in transplantationmedicine. In dermatology it is used as a corticosteroid-sparing agent. The pharmacokinetics of MMF areknown to vary by individual. Therapeutic dose monitoring of mycophenolic acid (MPA), the activemetabolite of MMF, is used as a guide in transplantation medicine, but limited data exist on the benefit ofmeasuring MPA levels in the management of dermatologic disease.

Objective: We sought to describe the use of MPA level monitoring in the management of dermatologicdisease.

Methods:We retrospectively searched for cases of patients who were treated with MMF for a dermatologiccondition at our tertiary care center, and who had at least 1 trough level measurement of MPA from January1, 2003, through November 30, 2009.

Results:Our search identified 24 patients treated with MMF for autoimmune bullous diseases, connectivetissue diseases, erythema multiforme, atopic dermatitis, or pyoderma gangrenosum who had at least 1 MPAtrough level measured. The range of MPA levels in patients who responded to therapy was 1.2 to 8 g/mLat a dose range of 1 to 3.5 g/d of MMF. Four cases were analyzed in detail to highlight the use of therapeuticdose monitoring in the management of dermatologic disease.

Limitations: This was a retrospective study.

Conclusion:We recommend monitoring MPA levels only in patients not responding to the standard 2-g/d

dosage of MMF. MPA levels can help the dermatologist to increase the dose in patients who have poorabsorption or to detect therapeutic noncompliance. ( J Am Acad Dermatol 2013;68:36-40.)

Key words: active metabolites; dermatologic disease; mycophenolate mofetil; mycophenolic acid;pharmacokinetics; therapeutic dose monitoring; transplantation medicine.

Mycophenolate mofetil (MMF) is alymphocyte-selective immunosuppressiveagent that inhibits de novo purine synthe-

sis via its active metabolite, mycophenolic acid(MPA).1 Although originally studied as a treatment

for psoriasis,

2

MMF received its final US Food andDrug Administration (FDA) approval in the 1990s forthe prevention of renal, cardiac, and hepatic allograftrejection.3 Like other immunosuppressive medica-tions used in the transplantation field, it also

demonstrated promise in the management of inflam-matory skin diseases. Currently, MMF is used as acorticosteroid-sparing agent in the management of

Abbreviations used:

FDA: Food and Drug AdministrationMMF: mycophenolate mofetilMPA: mycophenolic acid

From Department of Dermatology,a and Division of Clinical

Biochemistry and Immunology,b Mayo Clinic.

Funding sources: None.

Conflicts of interest: None declared.

Accepted for publication July 10, 2012.

Reprint requests: Rokea A. el-Azhary, MD, PhD, Department of

Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN

55905. E-mail: [email protected].

Published online August 13, 2012.

0190-9622/$36.00

2012 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2012.07.003

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mailto:[email protected]://dx.doi.org/10.1016/j.jaad.2012.07.003http://dx.doi.org/10.1016/j.jaad.2012.07.003mailto:[email protected]


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autoimmune blistering diseases, neutrophilic derma-toses, dermatitis, and connective tissue diseases.

After MMF administration, the absorbed drug israpidly hydrolyzed to MPA by esterases in the gas-trointestinal tract, plasma, liver, and kidneys.4 As aresult, the maximum concentration of MPA usuallyoccurs in 1 to 2 hours. MPA is inactivated in the liverby first-pass glucuronidation.The resultant phenolic glu-curonide of MPA is secretedin bile and recycled to theliver via enterohepatic recir-culation, which accounts fora second peak in MPA con-centration 6 to 12 hours afterMMF dosing. The phenolicglucuronide form of MPA isinactive and unable to pene-

trate the cell membrane un-less converted back to MPAby b-glucuronidase, an en-zyme present in high levelsin the gastrointestinal tractand epidermis.4 Patientswith severe renal impair-ment, bowel disease, liverdisease, and hypoalbuminemia may have alteredconcentrations of active MPA, which may lead totoxicity or treatment failure.

In clinical practice, therapeutic dose monitoring

for MMF is difficult and controversial. Although themeasurement of the area under the curve remainsthe best predictor of clinical effect, limited samplingstrategies are frequently used instead for practicalreasons. Despite the sampling of trough levels formany compounds, its applicability in the monitoringof MMF and its clinical effects may not be ofrelevance. In transplant recipients, the therapeuticdose of MMF is typically monitored on days 3 and 7,and once between days 10 and 14 posttransplanta-tion. If there is clinical necessity such as concern forrejection or adverse events, a week-3 or -4 post-

transplantation level may also be checked. Theoptimal range of trough MPA level to prevent rejec-tion in the transplant recipients was determined to befrom 1.2 to 3.5 g/mL.5

In dermatology, fixed dosages of 2 g/d are gen-erally recommended, without monitoring MPAlevels. Because of the well-known erratic absorptionof MMF, we sought to investigate whether a fixeddose is justifiable in all patients or whether, in someinstances, malabsorption may have a role in thedeemed failure of the drug. As a second objective,we questioned whether the therapeutic levelsneeded for prevention of transplant rejection are

similar to those needed for our dermatologicpopulation.

Here, we report on 24 patients treated with MMFfor various dermatologic diseases who had MPA levelmonitoring, with specific emphasis on 4 patients inwhom MPA trough level monitoring was instructivein their disease management.

METHODSThis study was reviewed

and approved by the MayoClinic Institutional ReviewBoard. We searched for andselected patients from ourpractice database who werebeing treated with MMF for adermatologic condition atMayo Clinic, Rochester, MN,

and who had at least1 trough level measurementof MPA from January 1, 2003,through November 30, 2009.Several of the cases identifiedwere selected for detailedanalysis because of their in-structive value.

MMF was generally given as a twice-daily dosage.To measure MPA trough levels, blood was drawn 12hours after the last evening MMF dose and before themorning dose. The method for quantitation of MPA

and MPA-glucuronide in biological specimens wasdeveloped in the toxicology and drug monitoringlaboratory at our institution. The analytes wereextracted by high-turbulence liquid chromato-graphy, followed by analysis using a liquidchromatograph-tandem mass spectrometer. Theconcentrations were calculated by comparison ofpeak-area ratio of the drug with deuterated internalstandards to those from the calibration curve. Thelimits of quantitation were determined to be 0.5 g/mL and 10.0 g/mL for MPA and MPA-glucuronide,respectively, and the upper end of the linear range is

12.5 g/mL and 250 g/mL for MPA and MPA-glucuronide, respectively. Interassay (between-run)variation was less than 10% throughout the analyticalrange.

Although area under the curve pharmacokineticsfor MMF is the most accurate way to determine totalMPA exposure, this method is not generally usedbecause it is impractical, requiring multiple blooddraws over several hours.6,7

RESULTSA total of 24 patients were identified who were

treated with MMF and had at least 1 MPA level drawn.

CAPSULE SUMMARY

d Mycophenolate mofetil, an

immunosuppressive agent used at a

standard dosage of 2 g/d, has variable

individual absorption.

d Review of 24 patients treated with

mycophenolate mofetil showed variable

levels of the active metabolite

mycophenolic acid, with a therapeuticrange of 1.2 to 8.0 g/mL.

d Monitoring of mycophenolic acid levels

in the treatment of dermatologic

diseases can serve multiple roles with

potential benefits.

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The diseases that were treated included immuno-bullous conditions, connective tissue diseases,atopic dermatitis, erythema multiforme, and pyo-derma gangrenosum. Table I shows the dose rangeof MMF and the respective MPA trough level for the24 patients. Patients who responded to treatment arethose who had remission with MMF as the soleimmunosuppressive agent and at a prednisone doseof 15 mg or less. Other patients not included in theresponder group were taking other immunosuppres-sants or were using high doses of prednisone whenthe MPA level was measured. The range of MPA inthe responding group was 1.2 to 8 g/mL at a doserange of 1 to 3.5 g/d of MMF.

Four patients with various diseases were selectedfrom the group and their cases were analyzed. Thesepatients used MMF as the sole immunosuppressiveagent and the prednisone dose was 15 mg or less

when the MPA level was measured. Of the 4 patientsanalyzed, only patient 2 reported gastrointestinaldiscomfort from the medication. However, this ad-verse effect was present only at an MMF dosagegreater than 4 g/d. No hematologic adverse effectswere reported, nor was increased infection attrib-uted to MMF use in any of the patients.

Patient 1A 34-year-old man with a history of recalcitrant

pemphigus vulgaris had a flare of his disease. He hadbeen receiving multiple treatments including azathi-

oprine, intravenous immunoglobulin, and cyclo-phosphamide. In the past, his treatment hadincluded very high doses (200 mg) of an oral corti-costeroid, which was tapered to a dosage of 10 mg/dbecause of severe adverse effects.

Because of the history of aseptic necrosis ofboth femurs and a shoulder joint, it was imperativeto try to taper the patient off corticosteroids. MMFwas started at 1.5 g twice a day. An MPA troughlevel checked a few weeks after drug initiation was1.3 g/mL. A repeated MPA trough level obtainedmonths later was less than 0.8 g/mL. Because of

disease persistence, the MMF dosage was increasedto 3.5 g/d, divided as 2 g and 1.5 g. However, an MPAtrough level checked 4 weeks after the dose increasewas less than 0.8 g/mL. The patient had been erraticin keeping his medical appointments, and hisdisease remained active and difficult to manage.When asked about noncompliance, the patientadmitted he was not very disciplined in taking hismedication. In this patients case, the MPA troughlevel confirmed the patients probable noncompli-ance with medication intake. Instead of discontinu-ing yet another immunosuppressive agent and

deeming it a therapeutic failure, further management

focused on patient education and emphasized med-ication compliance.

Patient 2A 48-year-old woman with a history of disfiguring,

recalcitrant, discoid lupus erythematosus was re-ferred for disease management. In the past, herdisease had been treated with oral and intralesionalcorticosteroid, thalidomide, and hydroxychloro-quine, with minimal clinical improvement.

Although low-dose oral corticosteroids were con-tinued, MMF was initiated at a dosage of 2 g/d, butwith no clinical improvement of her skin lesions. HerMMF dosage was subsequently increased to 3 g/d.

An MPA trough level obtained 6 weeks after the doseincrease was 1.8g/mL. Despite the therapeutic MPAlevels, her disease remained unresponsive. The MMFwas increased to 4 g/d, and a repeated MPA troughlevel was 3.2 g/mL. Although she noted someclinical improvement at this dosage, when the MMFwas further increased to 4.5 g/d to maximize herclinical response, she had gastrointestinal intoler-ance, and the dose was decreased to 3.5 g/d.Hydroxychloroquine was added to the MMF regi-men, and she continued to note clinical improve-ment and was successfully tapered off the oral

corticosteroid. At last follow-up, her disease

Table I. Mycophenolate mofetil dosage range andmycophenolic acid level in 24 patients

Disease

No. of

patients

Range of

MMF dosage,

g/d

Range of

MPA level,

g/mL*

Pemphigus vulgaris 9 1.0-3.5 \0.8-8.0

Respondersy 3 2.0-3.0 1.5-8.0

Connective tissue disease 6 1.0-4.5 1.2-3.2

Respondersy 0

Bullous pemphigoid 4 1.5-3.0 1.2-6.3

Respondersy 3 1.0-3.0 1.5-6.3

Atopic dermatitis 2 1.0-3.0 0.6-3.5

Respondersy 1 2.0 1.2

Epidermolysis bullosa

acquisita

1 2.0-3.5 1.8-5.3

Respondersy 0

Recurrent erythema

multiforme

1 1.5-2.0 0.6-1.3

Respondersy 0

Pyoderma gangrenosum 1 2.0-3.0 0.5-0.8Respondersy 0

Total 24 1.0-4.5 0.5-8.0

Respondersy 7 1.0-3.5 1.2-8.0

MMF, Mycophenolate mofetil; MPA, mycophenolic acid.

*Only MPA trough levels are included.yAll patients who responded were treated with MMF as sole

immunosuppressive agent and prednisone dose\15 mg/d.

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remained quiescent and was managed solely with ahigh-potency topical corticosteroid.

Patient 3A 49-year-old man with a diagnosis of mucous

membranee

predominant pemphigus was treatedwith an oral corticosteroid and referred for furthertreatment recommendations.

While taking 20 mg of prednisone, the patient wasstarted on an MMF dosage of 1.5 g/d, which wassubsequently increased over 1 year to 2 g/d and thento 3 g/d. His MPA trough levels at these doses were1.8, 2.5, and 8.0 g/mL, respectively. Remission wasobtained and maintained at the MPA level of 8.0 g/mL at 3 g/d of MMF. During that time his prednisonewas tapered to 5 mg/d. He is currently maintained on2.5 g/d of MMF and 5 mg of prednisone. The

intention is to continue the slow taper of prednisoneand then proceed with an MMF taper. The patienthad no evidence of hematologic abnormalities orinfections and tolerated the MMF dose well.

Patient 4A 58-year-old woman with a history of inflamma-

tory bowel disease, multiple bowel surgeries result-ing in a colostomy, and a 1-year history of pyodermagangrenosum ulcers on the breast, thigh, knee, andperineum was referred because of extension of theperineal pyoderma gangrenosum ulcer. Her ulcers

had been initially treated with prednisone and dap-sone, with resolution of all ulcers except the perinealulcer. At the time of hospital evaluation, she wastaking prednisone (10 mg/d) and dapsone (50 mg/d).The department of dermatology was consulted bythe surgical team to assist in the management of therecalcitrant pyoderma gangrenosum of the perinealregion.

Dapsone was discontinued because of anemiaand MMF 1 g twice a day (2 g/d total) was started. AnMPA trough level obtained on day 10 of treatmentwas subtherapeutic at 0.8 g/mL (reference range,

1.0-3.5 g/mL). The MMF dosage was increased to1.5 g twice a day (3 g/d total), and a repeated MPAtrough level was obtained on day 10 of the doseincrease. MPA level at this time was still low at lessthan 0.5 g/mL. There was no improvement in painor size of the ulcer. A peak MPA level checked 2hours after medication dose was 6.7 g/mL.Comparison of MPA trough and peak levels sug-gested adequate drug absorption but rapid metabo-lism and elimination, likely related to short bowelsyndrome. Therefore, an appropriate dosing recom-mendation such as 3 or 4 times daily dosing was

suggested, but the patient declined. MMF was

discontinued and she was switched to intravenousinfliximab, with excellent response.

DISCUSSIONMMF, which is FDA approved for use in transplant

recipients, is now widely used as a steroid-sparingagent in the management of dermatologic diseasessuch as autoimmune blistering diseases, neutrophilicdermatoses, dermatitis, and connective tissue dis-eases. Currently, the vast majority of transplantationcenters start with a fixed dosage of 2 g/d of MMF in12-hour intervals, either as monotherapy or in com-bination with other immunosuppressants such ascyclosporine, corticosteroids, or calcineurin inhibi-tors.8,9 Optimal trough MPA levels to prevent rejec-tion in transplant recipients are between 1.2 and3.5 g/mL.5 Studies have shown wide ranges of MPAlevels among patients receiving identical doses of

MMF.10 Factors implicated in this variation includekidney and liver function, ethnic status, and concur-rent medications such as calcineurin inhibitors. Incontrast to transplant recipients, dermatology pa-tients are usually not taking calcineurin inhibitorsand are generally healthy except for their skindisease, without associated kidney or liver dysfunc-tion. Dermatologists have adopted the use of a fixeddosage of 2 g/d of MMF without monitoring of theactive metabolite, MPA.

In the management of dermatologic disease suchas pemphigus vulgaris with MMF, a multicenter,

randomized, placebo-controlled trial by Beissertet al11 suggested that MMF at 2 g/d offers a betterrisk-benefit profile than 3 g/d in terms of responseand lower infection rates. No MPA levels weremeasured in that study. As shown in Table I and asdescribed in patients 2 and 3, an MMF dosage of 2 g/dmay be inadequate for some patients. There isreluctance among dermatologists to increase theMMF dose beyond the literature-recommendedvalue of 2 g/d, mostly because of potential adverseeffects. This reluctance, however, may be deprivingsome patients of a good drug that could help them.

Because individual variation in disease response iswell known to occur with MMF, measuring troughlevel of MPA would be extremely helpful. If it is low,this would encourage the use of a higher dosage ofMMF instead of the standard 2 g/d.

The wide variation in MPA levels among patientstaking the same dose of MMF has been related mostlyto erratic absorption of the drug. Many of ourpatients at standard doses of 2 g/d of MMF do noteven achieve the therapeutic drug level of 1.2 to3.5 g/mL MPA set for transplant recipients. Forexample, the patient with epidermolysis bullosa

acquisita (Table I) had MPA levels of 1.8 g/mL at

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2g/dofMMFand5.3 g/mL at 3.5 g/d of MMF, whichshe tolerated quite well. Others require a higherMMF dose and MPA levels above the transplantationupper limit of 3.5 g/mL to achieve remission, asshown in patients 2 and 3. Although response wasseen only in 7 of 24 patients, the results of our studysuggest an optimal range of MPA between 1.5 and 8.0g/mL. The upper limit of MPA regarding toxicity hasnot been determined. Although area under the curvemeasurements may have been more accurate in thedetermination of the total exposure to MPA, giventhe retrospective nature of our study, prospectivedetermination of the area under the curve was notfeasible.

Reports in the dermatology literature are contra-dictory. On one hand, some studies show thatPsoriasis Area and Severity Index scores, and psori-asis improvement in general, do not correlate with

MPA levels.12,13 On the other hand, prospectivestudies of systemic lupus erythematosus show thatthe individual variability in response is related todifferences in individual pharmacokinetics and notto the dose of MMF.14 They report a relationshipbetween MPA exposure and immunologic diseaseactivity markers. We agree with Roland et al14 thatthere is much individual variability in pharmacoki-netics that may result in different individual thera-peutic MPA levels necessary to induce remission.Some patients respond very well to lower doses ofMMF and have low MPA levels, as shown in Table I,

whereas others require much higher levels.Therefore, our standard dose in dermatology maybe related not only to the type of skin disease but alsoto the extent, severity, and recalcitrance of thatdisease. Other factors may also have a role in theadequacy of response, including the enterohepaticcirculation, and possibly even the level of MPA at thetarget cells in the skin.

In conclusion, this study highlights the multipleroles and potential benefits of MPA level monitoringin the treatment of dermatologic diseases. We are notrecommending that every patient taking MMF needs

MPA trough level monitoring; only those who do notappear to be responding at the standard dosage of2 g/d of MMF may benefit from obtaining an MPAlevel. This would help ascertain possible noncom-pliance, as in patient 1, or decreased gastrointestinalabsorption. Decreased absorption resulting in lowlevels of MPA would be a good rationale for increas-ing MMF dose rather than deeming it a therapeuticfailure. Increasing the dosage of MMF above therecommended 2 g/d in any situation should be donewith knowledge of the level of the active metabolite

before adding another immunosuppressive agent.This should help guide the physician in adjusting thedosage of MMF for better remission and diseasemanagement. In the future, prospective clinical trialswill be needed to determine the therapeutic range ofMPA in dermatologic diseases.

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10 Therapeutic dose monitoring of mycophenolate mofetil in dermatologic diseases (2).pdf