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`
`Mifepristone for Management of Cushing’s Syndrome
`
`Farah H. Morgan, and Marc J. Laufgraben
`
`Cushing’s syndrome is a debilitating endocrine disorder caused by elevated
`circulating glucocorticoid levels. Although uncommon, Cushing’s syndrome is
`associated with significant morbidity necessitating rapid reversal of hypercorti-
`solemia. Primary therapy for most patients with Cushing’s syndrome is surgi-
`cal, but many patients will require additional treatments with radiation or
`drugs. Although several options for drug therapy exist, few are readily available
`and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in-
`Class glucocorticoid receptor antagonist, was approved by the United States
`Food and Drug Administration in 2012 for use in Cushing’s syndrome to con-
`trol hyperglycemia in patients who are not surgical candidates or have not
`achieved remission from surgery. The drug is approved for oral once-daily
`administration. In its pivotal trial, 60% of patients responded to mifepristone
`with significant improvements in glycemic control and 38% had a reduction in
`diastolic blood pressure. The most common adverse events were nausea, fati-
`gue, headache, endometrial hyperplasia, and hypokalemia. Adrenal
`insuffi-
`ciency occurred in fewer than 5% of patients. The recommended starting
`dosage of mifepristone is 300 mg/day. The dosage may be increased every 2—
`4 weeks up to a maximum of 1200 mg/day, although it should not exceed
`20 mg/kg/day. Significant drug—drug interactions exist due to mifepristone’s
`effects on a number of cytochrome P450 enzymes. Despite its limitations, mife-
`pristone is a welcome addition and an appropriate alternative to the available
`drug therapy for Cushing‘s syndrome.
`Key Words: mifepristone, glucocorticoid receptor antagonist, Cushing’s syn-
`drome, Cushing’s disease, RU486.
`(Pharmacotherapy 2013;33(3):319-—329)
`
`Cushing’s syndrome is a rare but debilitating
`endocrine disorder caused by excess circulat-
`ing glucocorticoids. The excess glucocorticoids
`result from increased glucocorticoid production in
`the adrenal gland secondary to adrenal stimulation
`
`From the Division of Endocrinology, Diabetes and Metab-
`olism, Department of Medicine, Cooper Medical School of
`Rowan University, Camden, Ncwjersey (both authors).
`For questions or comments, contact Marc ]. faufgrabcn,
`Divisron' Head, DIViSion .Of Endocrinology, Diabetes and
`Metabolism, Cooper Medical School of Rowan UniverSity,
`Cooper University Hospital, 3 Cooper Plaza Suite 220,
`Camden, NJ
`08103;
`c-mail:
`laufgraben-marc@cooper
`healthedu.
`
`1
`
`or a primary adrenal tumor. For most forms of
`Cushing’s syndrome, the initial treatment is surgi-
`cal. However, a substantial proportion of patients
`will not be cured by surgery. Second-line therapy
`can include additional surgery, radiation, or phar-
`macologic agents. Previously available drugs have
`primarily been inhibitors of adrenal steroid syn-
`thesw’ and .[lle use Of these agents has beep limited
`by aVallablllty and tolerabillty.
`leeprlstone, a
`first-in-class glucocorticoid receptor antagonist,
`was appI‘OVCd by the United States Food and Drug
`Administration (FDA) in 2012 for use in patients
`.
`,
`_
`,
`Wlth
`hyperglycemia
`secondary
`‘0 CUShmgS
`Syndrome. With approval of this new agent, prac-
`titioners need a thorough understanding of its
`TEVA1 030
`
`1
`
`TEVA1030
`
`

`

`320
`
`PHARMACOTHERAPY Volume 33, Number 3, 2013
`
`pharmacology, pharmacokinetics, pharmacody-
`namics, clinical efficacy, indications for use, and
`limitations.
`
`Cortisol: Normal Physiology
`
`Secretion of cortisol is maintained by a clas—
`sic endocrine feedback system. Cortisol pro-
`duction occurs in the zona fasciculata cells of
`the adrenal cortex. These cells are stimulated
`by
`adrenocorticotrophic
`hormone
`(ACTH),
`which is secreted by corticotroph cells in the
`anterior pituitary gland. ACTH production is
`stimulated by corticotrophin—releasing hormone
`(CRH) produced in the paraventricular nucleus
`of the hypothalamus. Circulating cortisol
`then
`provides negative feedback to inhibit produc-
`tion of CRH and ACTH. Thus, cortisol dynam-
`ics depend on normal hypothalamic, pituitary,
`and adrenal function—the hypothalamic-pitui—
`tary—adrenal axis
`(Figure 1). Normal cortisol
`levels follow a circadian rhythm with a peak in
`the early morning (7:00—9:00 AM.) and a nadir
`at 11:00 P.M. CRH production is further regu-
`lated by physiologic and emotional stress.1
`Cortisol is necessary to sustain life. It plays a
`role in multiple essential
`functions including
`carbohydrate, protein, and lipid metabolism and
`vascular tone and blood pressure maintenance.
`It
`is also involved in the immune system and
`
`Stress
`
`\
`
`Circadian rhythm
`
`/
`
`>
`
`llypothalamus
`
`CRH
`
`Pituitary
`
`ACTH
`
`Adrenal Cortex
`
`Cortisol
`
`Figure 1. Normal regulation of the hypothalamic-pituitary-
`adrenocortlcal
`axis.
`'
`2 ACTH = andrenocorticotrophic
`hormone; CRH = corticotrophin-releasing hormone.
`
`2
`
`their
`responses to stress. Glucocorticoids exert
`actions mainly through binding at the glucocor-
`ticoid receptor, a member of the thyroid and
`steroid hormone receptor superfamily of nuclear
`transcription factors. As would be expected, the
`glucocorticoid receptor is expressed widely in
`peripheral
`tissues
`and brain regions. Many
`glucocorticoids,
`including cortisol,
`also have
`affinity for the mineralocorticoid receptor. How-
`ever, under normal circumstances,
`the renal
`mineralocorticoid receptor is “protected” from
`cortisol binding by the local activity of type 2
`llB—hydroxysteroid dehydrogenase (1 1 B—HSD),
`which converts cortisol
`to cortisone and does
`not bind to
`the mineralocorticoid receptor.
`Under physiologic circumstances, aldosterone is
`the primary activator of the mineralocorticoid
`receptor;
`its activation promotes sodium reten-
`tion (and therefore maintenance of blood pres—
`sure) and potassium excretionl’ 2
`Deficiency of cortisol results in the signs and
`symptoms of adrenal insufficiency, which can vary
`in severity from fatigue and anorexia to hypoten-
`sion and hypoglycemia to shock and death. Corti-
`sol excess results in Cushing’s syndrome.
`
`Cushing’s Syndrome
`
`the result of excess
`Cushing’s syndrome is
`circulating glucocorticoids. Exogenous, or iatro-
`genic, Cushing’s syndrome is common and typi-
`cally results from the use of supraphysiologic
`doses of glucocorticoids
`to treat pulmonary,
`rheumatologic, hematologic, or other disorders.
`Endogenous Cushing’s syndrome is
`rare and
`results from inappropriate activation of either the
`pituitary gland or adrenal glands,
`leading to
`increased circulating cortisol levels. The majority
`of cases are caused by an ACTH-secreting tumor
`of the pituitary gland (i.e., Cushing’s disease).
`Cushing’s syndrome may also result from ectopic
`secretion of ACTH by neoplasms such as small
`cell lung cancer and carcinoid tumors; rarely, a
`tumor may secrete CRH. Cushing’s syndrome can
`also result from benign, malignant, or hyperplas—
`tic diseases of the adrenal glands that secrete
`cortisol in the absence ofACTH stimulation.3'5
`
`The excess cortisol seen in Cushing’s syn-
`drome results in hypertension, hyperglycemia,
`obesity,
`and a myriad
`of other problems
`(Table 1).5 These complications lead to signifi-
`cant morbidity related to illness and twice the
`mortality rate in patients with Cushing’s syn-
`drome compared to the general population.6
`Diabetes mellitus and hypertension are the most
`
`2
`
`

`

`MIFEPRISTONE FOR CUSHING’S SYNDROME Morgan et al
`Table 1. Signs and Symptoms of Cushing‘s SyndromeS
`Other
`
`321
`
`Symptoms
`
`Depression
`
`Fatigue
`Weight gain
`
`Signs
`
`Obesity (especially
`central obesity)
`Facial plethora
`Moon facies
`
`Conditions
`
`Hypokalemia
`
`Hypertension
`Diabetes
`mellitus
`
`Insomnia
`Muscle weakness
`
`Irritability
`
`Irregular menses
`Back pain
`
`Osteoporosis
`Renal calculi
`
`Easy bruising
`Striae (especially wide
`violaceous striae)
`Proximal myopathy
`Dorsocervical fat pad
`Supraclavicular fat pads
`Edema
`Acne
`Thin skin
`Ilirsutism
`Female balding
`
`important predictors of death.6 Hypertension
`occurs in 80% of patients with Cushing’s syn—
`drome and is thought to be caused by the effect
`of cortisol on both the glucocorticoid receptor
`and the mineralocorticoid receptor."r The excess
`cortisol overwhelms the ability of type 2 HB-
`HSD to convert it to cortisone, and thus cortisol
`has access to and activates the mineralocorti-
`coid receptor.
`Impaired glucose tolerance or
`type 2 diabetes also occurs in 80% of patients as
`a
`result of
`increased insulin resistance and
`impaired
`insulin
`secretion.(7 Glucocorticoids
`increase insulin resistance through actions on
`liver, skeletal muscle, and adipose tissue. The
`net result of increased liver gluconeogenesis and
`decreased glucose uptake in skeletal muscle and
`adipose tissue is hyperglycemia.6 Impaired insu—
`lin secretion also occurs as a result of glucocor-
`ticoids binding to pancreatic B cells, resulting in
`impaired B-cell function.6 This combined effect
`causes hyperglycemia that can be very difficult
`to treat, often requiring escalating doses of insu-
`lin for appropriate management.
`
`Diagnosis of Cushing’s Syndrome
`
`Because of the complexity of the screening
`and diagnostic algorithms for Cushing’s
`syn-
`drome, referral
`to an endocrinologist is appro-
`priate when the disorder is suspected. Accurate
`diagnosis of Cushing’s
`syndrome
`is
`critical
`to avoid unnecessary testing, procedures, and
`expenditures.5' 7
`testing for
`Before
`considering biochemical
`endogenous Cushing’s syndrome, it is important
`to rule out exogenous glucocorticoid exposure
`
`Initial
`causing iatrogenic Cushing’s syndrome.
`testing can include measurement of 24-hour
`urine free cortisol,
`late-night salivary cortisol
`collected at 11:00 P.M. or 12:00 A.M., or early
`morning cortisol after dexamethasone 1 mg the
`previous evening at 11:00 P.M. (overnight dexa-
`methasone l-mg suppression test). When an
`abnormal result is obtained, a physiologic cause
`of hypercortisolemia,
`such as depression or
`other psychiatric illness, alcohol abuse, physical
`stress, malnutrition, or pregnancy, should be
`excludeds’ 8’ 9
`.
`After establishment of the diagnosis of Cushing’s
`syndrome, the endocrinologist must determine the
`source of the hypercortisolemia. A low or unde—
`tectable ACTH level should raise the suspicion for
`an ACTH-independent source, and imaging of the
`adrenal glands should be performed. An elevated
`or
`nonsuppressed
`(“inappropriately
`normal”)
`ACTH level reflects an ACTH-dependent source of
`hypercortisolemia. A combination of noninvasive
`biochemical
`testing (high-dose dexamethasone
`testing or CRH stimulation), pituitary magnetic
`resonance imaging, and, often,
`inferior petrosal
`sinus sampling for ACTH may be necessary to
`determine if the source is an ACTH-secreting
`1
`pituitary adenoma or a nonpituitary tumor with
`ectopic ACTH production.5‘
`
`Treatment Options for Cushing’s Syndrome
`
`Treatment of Cushing’s syndrome is dependent
`on the identified source of the disorder. Patients
`with cortisol-secreting adrenal adenomas are usu-
`ally cured with unilateral adrenalectomy, whereas
`patients with adrenocortical carcinoma often have
`persistent or recurrent disease after surgery due
`to local invasion or metastases. In patients with
`the ectopic ACTH syndrome, initial treatment is
`directed at
`the underlying neoplasm. Medical
`therapies are often needed in patients with persis-
`tent hypercortisolemia.
`In patients with Cushing’s disease (ACTH-
`secreting pituitary adenomas), who make up the
`majority of patients with Cushing’s syndrome,
`the primary treatment modality is transsphenoi-
`dal surgery, which results in remission rates of
`50—80%.3’ ”T14 If there is failure to attain remis-
`sion after initial surgery or if the disease recurs
`later, second-line interventions include repeat
`surgery,
`radiotherapy, bilateral adrenalectomy,
`or pharmacologic therapy?“ 13‘ 15
`Medical therapy for hypercortisolemia is pro-
`vided to patients who are unable to undergo
`surgery because of another illness,
`to patients
`
`3
`
`

`

`,v
`
`therapy
`
`
`
`
`
`endometrialhyperplasra,nausea
`
`Expensive,difficulttomonitor
`
`
`
`Hypokalemia,adrenalinsufficiencv
`
`
`type5receptorsGlucocorticoidreceptorantagonism
`
`322
`
`PHARMACOTHERAPY Volume 33, Number 3, 2013
`
`
`
`Intravenousadministrationonly
`
`Sedation
`
`
`
`
`
`Limitedavailabilityandefficacy
`
`withanotheragentSlowonset
`
`
`
`
`
`
`
`Rash,fever,dizziness,depression
`
`
`
`Druginteractionsduetoinhibitionof CYP3A
`
`
`
`Hepatotoxicity,hypogonadism
`
`
`
`Inhibitionofcortisolsynthesis:11B-hydroxlase,
`
`Comments
`
`
`
`AdverseReactions
`
`MechanismofAction/SiteofAction
`
`DoseRange
`
`200mgb.i.d.—400mg
`
`t.i.d.
`
`Limitedavailability,oftencombined
`
`
`
`
`
`Hypertension,edema,hypokalemia,
`
`
`
`
`
`Gastrointestinaleffects,ataxia,
`
`hirsutism
`
`
`
`17-hydroxylase,andC17,20lyseInhibitionofcortisolsynthesis:
`
`250—1500mgq.i.d.
`
`1IB-hydroxylaseInhibitionofcortisolsynthesis:
`
`500—3000mgt.i.d.
`
`confusion
`
`
`
`IlB—hydroxylaseandcholesterolsidechains
`
`who have failed to achieve remission with other
`treatment modalities, as a bridge to radiotherapy
`or surgery, or as a palliative option. A number
`of potential
`targets exist
`for medical
`therapy,
`including inhibition of steroidogenesis,
`inhibi-
`tion of ACTH secretion, and steroid receptor
`antagonism. The most commonly used agents
`are steroidogenesis inhibitors such as ketoconaz-
`ole, metyrapone, and mitotane. Other agents in
`this class include aminoglutethimide and etomi-
`date (Table 2)}, 13, 16-20
`Steroidogenesis inhibitors are considered adre-
`nal—directed medical
`therapy because they con—
`trol cortisol production by directly decreasing
`adrenal hormone production. Ketoconazole is
`the most commonly used steroidogenesis inhibi-
`tor because of its availability and relatively rapid
`onset of action. Kctoconazole was developed as
`an antifungal drug. It inhibits cortisol synthesis
`by preventing cholesterol Side chain cleavage,
`inhibiting cytochrome P450 enzyme 17,20-lyase,
`and inhibiting llB-hydroxylase,
`the
`enzyme
`involved in the final step of cortisol synthesis.
`Its major limiting adverse effect is elevated liver
`enzyme levels, which occur in up to 10% of
`patients. It can also cause hypogonadism in meg
`because of inhibition of testosterone synthesis.
`’
`19«21
`
`Metyrapone blocks the production of corti-
`sol
`through inhibition of
`IIB-hydroxylase.
`This effectively reduces hypercortisolemia, but
`because metyrapone is
`specific for
`a
`single
`enzyme late in the steroid biosynthesis path-
`way,
`there is often a dramatic rise in steroids
`formed proximal
`to IIB-hydroxylase, particu-
`larly 11—deoxycortisol, a mineralocorticoid that
`causes the frequent adverse effects of hypokale-
`mia, edema, and hypertension. An increase in
`adrenal
`androgens
`can
`cause hirsutism in
`women. In an effort
`to limit
`the accumulation
`of precursor
`steroids, metyrapone
`is often
`used in combination with other medical thera~
`pies such as ketoconazole. It is currently avail-
`able in the United States directly from the
`manufacturer.16' 19’ 20’ 22
`Mitotane is used most often for the manage-
`ment of adrenocortical carcinoma.
`It works
`through the inhibition of multiple enzymes19
`and, unlike other agents,
`is directly cytotoxic
`to adrenocortical cells. Undesirable features of
`
`mitotane are its delayed onset of action and
`dose-limiting
`gastrointestinal
`effects.
`Serious
`neurologic effects, including ataxia, vertigo, and
`confusion, also occur at higher doses. These
`adverse effects limit the tolerability of mitotane,
`
`4
`
`
`
`Table2.DrugTherapyfortheTreatmentofCushing’sSyndrome3‘13’1640
`
`
`
`
`
`
`
`
`
`
`
`IIItrialsLimitedefficacyLimitedefficacyInphase
`
`
`
`
`
`Nausea,hypotension
`
`
`
`Nausea,hypotension
`
`Hyperglycemia
`
`
`
`
`
`IIB-hydroxylaseand18hydroxylaseInhibitionofcortisolsynthesis:
`0.1—0.3mg/kg/hr
`
`ylase,l7hydroxylase,
`
`
`lIb-hvdrox
`
`andC17,20IyseDopamineagonist
`
`
`
`Dopamineagonist
`
`2.5—40mg/day1—2mg/wk
`
`Somatostatinanalog,somatostatin
`
`
`600—900ugbid.
`
`300—1200mg/day
`
`
`
`
`
`Inhibitionofcortisolsynthesisandsidechain
`cleavage:
`
`2000mgqid.
`
`
`
`250mgb.i.d.-—
`
`Aminoglutethimide
`
`Ketoconazole
`
`Drug
`
`Metyrapone
`
`Mitotane
`
`
`
`CYP=cytochromeP450.
`
`BromocriptineCabergolinePasireotide
`
`Mifepristone
`
`Etomidate
`
`4
`
`

`

`MIFEPRISTONE FOR CUSHING’S SYNDROME Morgan et al
`
`323
`
`and it must often be used in combination
`
`with another drug to attain more rapid control
`of hypercortisolemia.3’ 19’ 23
`Aminoglutethimide and etomidate are steroi-
`dogenesis inhibitors that are used infrequently
`due
`to
`their
`limitations. Aminoglutethimide,
`which works by inhibiting the conversion of
`cholesterol
`to pregnenolone,
`is neither particu-
`larly effective as monotherapy nor readily avail-
`able in the United Statesm’
`19 Etomidate, an
`intravenous agent used for anesthesia induction,
`inhibits cholesterol side chain cleavage and 11B-
`hydroxylase.
`It has been used in emergent set-
`tings for the rapid control of hypercortisolemia
`but
`is not practical for routine use due to its
`sedative effects.16' 19’ 24
`
`Drugs that suppress ACTH secretion have
`been investigated for use in the management of
`Cushing’s disease. Among these are dopamine
`agonists and somatostatin analogs. Dopamine
`agonists are potentially attractive agents for the
`treatment of Cushing’s syndrome because of
`the potential
`for decreased prevalence of glu-
`cose intolerance and diabetesf" 13’
`16’
`25 but
`results have been variable and few patients
`with Cushing’s syndrome experienced sustained
`improvement after receiving dopamine agonist
`therapy.]3’ 19’ 20 Bromocriptine causes an acute
`decrease in ACTH, although this effect
`is not
`sustained over time with repeated dosing.
`Octreotide, a somatostatin analog that pre-
`dominantly acts on type 2 somatostatin recep-
`tors,
`is
`largely ineffective in lowering ACTH
`levels.13‘
`16 A newer multiligand somatostatin
`analog, pasireotide (SOM230), has been demon—
`strated to inhibit ACTH release in human corti-
`
`cotroph cells through interaction with type 5
`somatostatin receptorsfi‘
`16’
`26
`Its use has
`resulted in reduced urine free cortisol levels and
`improved features of Cushing’s
`syndrome in
`phase II and III studies, but it appears to have
`the undesirable effect of hyperglycemia,” 27
`possibly caused by direct
`inhibition of insulin
`and incretin hormone secretion.
`
`Mifepristone
`
`Mifepristone (RU486), a derivative of the syn-
`thetic progestin norethindrone, was discovered
`in the 19805 at the French pharmaceutical com-
`pany Roussel-Uclaf as part of a special research
`project
`to
`develOp
`antiglucocorticoid
`com-
`pounds.28 Its antiprogestin effects were quickly
`recognized, and it was developed as an abortifa-
`cient because of its effectiveness in pregnancy
`
`termination, particularly when combined with a
`prostaglandin. Other investigated uses that take
`advantage of its antiprogesterone activity include
`the treatment of meningioma and breast cancer.
`Unfortunately,
`research on mifepristone has
`been hindered by the controversy surrounding
`its use as an abortion pill.28
`Mifepristone is a selective antagonist of the
`progesterone receptor at lower doses and blocks
`the glucocorticoid receptor at higher doses.18
`Mifepristone occupies glucocorticoid receptors
`with an affinity that is 4-fold higher than that of
`dexamethasone and 18-fold higher than that of
`cortisol.28 After binding,
`it
`inhibits transcrip-
`tional activation of the glucocorticoid receptor,
`thereby decreasing the physiologic effects of hy-
`percortisolemia. It blocks both central (negative
`feedback on CRH and ACTH) and peripheral
`actions of cortisol.28 Antagonism of negative
`feedback of cortisol results in increased circulat-
`ing ACTH and cortisol levels.28’ 20 It has little
`affinity for
`the mineralocorticoid receptor and
`estrogen receptors but is a weak antiandrogen.
`Mifepristone is also a weak glucocorticoid ago-
`nist,
`roughly
`1/250th
`of
`that
`of
`cortisol,
`although this weak effect is unlikely to prevent
`adrenal insufficiency.2830
`
`Pharmacolzinetics and Pharmacodynamics
`
`readily absorbed after oral
`Mifepristone is
`ingestion with a bioavailability exceeding 30%.31
`Time to peak plasma concentrations after oral
`administration of a single dose is
`1—2 hours,
`increasing to 1—4 hours with repeated doses.
`Food increases
`the plasma concentrations of
`mifepristone. Mifepristone has three active metab-
`olites, all of which have high affinity and antago_
`nism for the glucocorticoid receptor (~50% of
`that of mifepristone). Cytochrome P450 (CYP)
`3A is involved in the metabolism of mifepristone.
`Two of the known active metabolites are a result
`of demethylation, whereas the third is a result of
`hydroxylation. Mean plasma concentration of
`these metabolites peaks between 2 and 8 hours
`after multiple doses of the drug and eventually
`exceeds that of mifepristone.18 Therefore, drug
`interactions affecting enzyme metabolism may
`affect the degree of antagonism of the glucocorti-
`coid receptor. Time to steady state with repeated
`daily dosing is 2 weeks. Mifepristone has a very
`long elimination half-life of 85 hours
`after
`repeated dosing.18
`exist
`interactions
`Significant
`drug—drug
`because of mifepristonc’s effects on several CYP
`
`5
`
`

`

`324
`
`PHARMACOTHERAPY Volume 33, Number 3, 2013
`
`enzymes. For example, CYP3A is involved in the
`metabolism of mifepristone and mifepristone
`also both inhibits and induces CYP3A. There-
`fore, drugs
`that are metabolized by CYP3A
`should
`be
`avoided
`or
`used With
`caution
`(Table 3). When a once-daily dose of mifepri-
`stone 1200 mg was coadministered with simvast-
`atin 80 mg for 10 days in healthy volunteers,
`there was an 18-fold increase in the maximum
`lasma concentration (Cmax) of simvastatin acid
`and a 7-fold increase in the Cmax of simvastatin,
`significantly increasing the risk of toxicity of
`this drug. 8 Drugs
`that
`inhibit CYP3A can
`increase mifepristone levels, and a dose reduc-
`tion of mifepriStone may be required (Table 3).
`Coadministration 0f mifepristone and CYP3A in-
`ducers has not been studied. Other enzymes
`affected by mifepristone are CYP2C8/2CQ and
`CYP2B6. Drugs metabolized by these pathways
`should be used with caution (Table 4). The
`Cmax of iluvastatin 40 mg was increased 1.76—
`fold when coadministered with mifepristone
`1200 mg.18 Because of the long half-life of mife-
`pristone and time to reach steady state, dosage
`adjustment of drugs with potential
`interactions
`should not occur more frequently than every
`2 weeks. Drugs that are contraindicated for use
`with mifepristone can be safely initiated 2 weeks
`after the discontinuation of mifepristone.18
`Mean exposure (plasma concentration over
`time)
`to mifepristone (evaluated with multiple
`1200-mg doses for 7 days) increased by 31% in
`patients with a creatinine clearance less than
`30 ml/min compared to patients with normal
`renal
`function (creatinine clearance > 60 my
`min). There was large variability among subjects
`
`Table 4. Drugs that Interact with Mifcpristone Through
`
`CYP2C8/2C9 and CYPZB6'“
`
`Drugs Metabolized
`Drugs Metabolized by
`
` CYP2C8/2C9 by CYPZBé
`Use lowest dose and
`Not studied—use lowest
`monitor closely
`dose
`Fluvastatin
`Bupropion
`NSAIDS
`Efavirenz
`Warfarin
`Repaglinide
`CYI’ = cytochrome P450; NSAIDs = nonsteroidal anti-inflamma-
`tory drugs,
`
`in the exposure of mifepristone and its metabo-
`lites. The pharmacokinetics of mifepristone in
`patients with moderate hepatic impairment was
`found to be similar to that in patients with nor—
`mal hepatic function. The pharmacokinetics in
`patients with severe hepatic impairment has not
`been studied.18
`
`Clinical Efficacy
`
`Initial information regarding efficacy of mife—
`pristone for use in Cushing’s syndrome came
`from case reports. In 1985, a patient with Cush-
`ing’s syndrome secondary to ectopic ACTH secre-
`tion was treated with mifepristone.32 The initial
`dosage was 5 mg/kg/day because it was known
`that a dosage of 6 mg/kg/day prevents morning
`adrenal suppression from dexamethasone 1 mg.
`The dosage was increased in 5-mg/kg/day incre-
`ments every 1—2 days to a maximum of 20 mg/kg/
`day. Treatment resulted in resolution of clinical
`effects of Cushing’s syndrome, redistribution of
`fat, and improvement
`in hyperglycemia and
`
`Limit mifepristone to 300 mg/day
`
`Azole antifungals
`Protease inhibitors
`
`Table 3. Sample List of Drugs or Foods that Interact with Mifcpristone Through CYP4503A“l
`CYP3A
`Drugs Metabolized
`CYP3A Inhibitors
`Induccrs
`by CYP3A
`Do not use (has not
`Use alternative drug or administer
`been studied)
`lowest dose and/or decrease frequency
`Rifabutin
`Cyclosporine
`Phenobarbital
`Dihydroergotamine
`Ergotamine
`Fentanyl
`Pimozide
`Quinidine
`Sirolimus
`Tacrolimus
`Simvastatin
`Lovastatin
`
`Macrolides
`Mibefradil
`Nefazodone
`Conivaptan
`Caution—use lowest effective dose of mifepristone
`lmatinib
`Aprepitant
`Ciprolloxacin
`Grapefruit juice
`Nondihydropyridine CCBs
`CCBs = calcium channel blockers; CYP = cytochrome P450.
`
`Phenytoin
`Carbamachine
`St. john’s wort
`Rifampin
`
`6
`
`

`

`MIFEPRISTONE FOR CUSHING’S SYNDROME Morgan et al
`
`325
`
`hypertension. Fasting glucose and 2-hour glucose
`levels after ingestion of glucose 100 g normalized
`with the highest doses.
`In contrast,
`levels of
`ACTH, serum cortisol, and urine free cortisol
`remained
`elevated. Treatment was
`stopped
`because of the limited availability of mifepristone.
`A cases series of 10 patients with Cushing’s
`syndrome treated with mifepristone was pub-
`lished in 1989.28’ 33’ 34 Six of the 10 patients
`who received mifepristone 5—22 mg/kg/day had
`their symptoms of hypercortisolemia alleviated.
`Patients” hypertension improved, with reduction
`in mean blood pressure. Carbohydrate metabo-
`lism also improved, as evidenced by reduction
`in 2-hour plasma glucose levels during oral glu-
`cose tolerance testing. Two of three men com-
`plained of gynecomastia and impotence, whereas
`only two patients developed adrenal
`insuffi-
`ciency.3“1
`Subsequent studies ensued to elucidate the
`drug’s
`antiglucocorticoid effects
`and relative
`safety for long-term treatment. In 1994, mifepri-
`stone 200 mg/day was administered to 10 healthy
`volunteers for 8 consecutive days. The investiga-
`tors found heightened activation of the hypotha-
`lamic-pituitary-adrenal axis with elevations in
`plasma cortisol, urinary cortisol, and ACTH lev-
`els, although there was no evidence of clinical
`symptoms. Adrenocortical reserves seemed to be
`preserved as evidenced by the ability to further
`increase circulating cortisol with ACTH stimula-
`tion.29 In 1995, the antiglucocorticoid effects of
`mifepristone were evaluated in eight healthy
`men.35 This study evaluated subjects during the
`infusion of cortisol after the ingestion of mifepri-
`stone 600 mg or placebo and during the infusion
`of normal saline with placebo or mifepristone.
`The increase in plasma glucose levels seen with
`cortisol
`infusion plus placebo was not demon-
`strated when cortisol was administered after mife-
`pristone ingestion. Although this study involved
`only healthy men and was limited by the small
`number of patients studied, it supported the con-
`cept that mifepristone may suppress the effects of
`hypercortisolemia on glucose.
`In 2009,
`results from a retrospective study
`were published: 20 patients with Cushing’s syn-
`drome due to malignant or benign causes were
`treated with oral mifepristone 400—2000 mg/day
`for 5 days to 24 months.36 The median initiation
`dose was 400 mg with a median maximum dose
`of 600 mg/day. Eight of the 12 patients with
`adrenocortical carcinoma, most of whom had
`failed surgery, cytotoxic chemotherapy, and/or
`mitotane as well as other drug therapy, had
`
`rapid improvement within the first month of ini-
`tiation of mifepristone. Seven
`of
`these
`12
`patients developed hypokalemia, although this
`required cessation of therapy in only 1 patient.
`All three patients with ectopic ACTH secretion
`had improvement in clinical symptoms, and the
`two patients with diabetes
`required a
`rapid
`decrease in their insulin dose. Three of four
`patients with Cushing’s disease had improve—
`ment
`in clinical
`signs of hypercortisolemia;
`levels of ACTH and cortisol increased in all four
`
`treated had bilateral
`patients. The last patient
`adrenal hyperplasia. Hypertension and signs of
`hypercortisolemia improved within 3 months of
`therapy, and hemoglobin AIC (AIC) was reduced
`from 7.1% to 6.4%. Overall,
`the investigators
`found improvement in clinical symptoms in 15
`of the 20 patients along with improvement
`in
`blood glucose levels in 4 of 7 patients with
`hyperglycemia. Serious adverse effects included
`signs of adrenal insufficiency in 3 patients and
`hypokalemia in 11 patients.
`Recently, an open-label, 24-week, multicenter
`clinical study evaluated safety and efficacy of mi-
`fepristone for
`the treatment of Cushing’s syn-
`drome; the results led to the drug’s approval by
`the FDA in 2012.37 A separate open-label exten-
`sion of this trial is ongoing. The study enrolled
`50 patients with continued biochemical and clin-
`ical evidence of hypercortisolemia after
`failed
`multimodality therapy, largely with surgery and/
`or radiotherapy. Endogenous hypercortisolemia
`was defined as elevated urine free cortisol levels
`measured from at least two 24-hour collections
`and elevated late-night salivary cortisol
`levels
`and/or lack of suppression with dexamethasone.
`Inclusion criteria were associated type 2 diabe-
`tes,
`impaired glucose tolerance diagnosed from
`an oral glucose tolerance test, or hypertension
`with at
`least
`two other signs or symptoms of
`Cushing’s syndrome. Exclusion criteria included
`an A1C greater
`than 11%, poorly controlled
`hypertension
`(blood
`pressure > 170/110 mm
`Hg), use of drugs to treat hypercortisolemia
`within 1 month, uncorrected hypokalemia, and
`uncontrolled thyroid disease. Women with evi-
`dence of endometrial hyperplasia, cancer, or pol-
`yps
`and those with an intact uterus who
`required anticoagulation or had hemorrhagic
`disorders were also excluded. Initiation or addi—
`
`impaired glucose
`tions to therapy for diabetes,
`tolerance, depression, hyperlipidemia, or hyper-
`tension were not allowed, with the exception of
`the addition of a mineralocorticoid antagonist
`for the treatment of hypokalemia.
`
`7
`
`

`

`326
`
`PHARMACOTHERAPY Volume 33, Number 3, 2013
`
`Fifty patients were enrolled at 17 centers.
`Forty-three of the patients had Cushing’s dis-
`ease, 4 had ectopic ACTH tumors, and 3 had
`adrenal carcinoma. Patients were separated into
`a diabetes cohort (29 patients) and a hyperten-
`sion cohort (21 patients), and efficacy was eval-
`uated in each cohort. Treatment was initiated
`with mifepristone 300 mg/day, which could be
`increased to 600 mg after
`2 weeks. Further
`increases by 300-mg increments were allowed
`every 4 weeks with a maximum dosage of 900—
`1200 mg/day based on weight. The mean :1: SD
`dose at the final study visit was 732 :l: 366 mg/
`da .
`lln the diabetes cohort, patients were required
`to have received stable antidiabetic regimens
`before enrollment and the regimens could not
`be advanced during the study. The primary end
`oint was a reduction in the area under the
`curve (AUC) for glucose of at least 25% as mea-
`sured with an oral glucose tolerance test. This
`test was chosen because it could be used for
`evaluation of patients with either diabetes or
`impaired glucose tolerance. In the hypertension
`cohort, the primary end point was the change in
`diastolic blood pressure from baseline to week
`24 with response defined as a reduction of at
`least 5 mm Hg. Secondary end points included
`other clinical responses compared to baseline as
`evaluated by an independent data review board
`at weeks 6, 10, 16, and 24. This board evaluated
`glucose homeostasis, blood pressure, lipid levels,
`weight and body composition, clinical appear-
`ance,
`strength,
`and neuropsychological
`and
`quality of life scales using validated methods.
`Thirty-four patients completed the study: 20 in
`the diabetes cohort and 14 in the hypertension
`cohort. Reasons
`for withdrawal were adverse
`events (7), death (2), withdrawn consent (5), and
`other (2). Deaths were related to progression of
`underlying malignancy. A modified intent-to-treat
`analysis was used. All patients who received at
`least 30 days of the study drug were included in
`the analysis. Of the 25 patients in the diabetes
`cohort who received mifepristone for at
`least
`30 days, 60% (15 patients) responded with a 25%
`or greater reduction in glucose AUC during stan-
`dard glucose tolerance testing (p<0.0001). Eigh-
`teen of the patients (72%) in the diabetes cohort
`had at least a 25% reduction in glucose AUC or
`were able to reduce antidiabetic therapy. Mean
`reduction in AlC was
`1.1% from baseline
`(p<0.001), and 6 of 12 patients with an AIC
`greater than 7% at baseline had an AIC of 6% or
`less by the end of the trial. Mean :l: SD fasting 8
`
`from
`reduced
`levels were
`glucose
`plasma
`149 :1: 74.7 mg/dl at baseline to 104.7 i 37.5 mg/
`d1 at 24 weeks (p<0.03). The doses of antidiabetic
`drugs were reduced in 7 of 15 patients. Of the 12
`patients receiving insulin, 5 were able to reduce
`their insulin doses by at least 50%.37
`In the hypertension cohort, 8 (38.1%) of 21
`pat