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.
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
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-
From the Division of Endocrinology, Diabetes and Metab- olism, Department of Medicine, Cooper Medical School of Rowan University, Camden, New Jersey (both authors).
For questions or comments, contact Marc J. Laufgraben, Division Head, Division of Endocrinology, Diabetes and Metabolism, Cooper Medical School of Rowan University, Cooper University Hospital, 3 Cooper Plaza Suite 220, Camden, NJ 08103; e-mail: [email protected] health.edu.
thesis, and the use of these agents has been limited by availability and tolerability. Mifepristone, a first-in-class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration (FDA) in 2012 for use in patients with hyperglycemia secondary to Cushing’s syndrome. With approval of this new agent, prac- titioners need a thorough understanding of its
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 A.M.) 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
responses to stress. Glucocorticoids exert their 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 11b-hydroxysteroid dehydrogenase (11b-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 excretion.
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 is the result of excess 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 of ACTH stimulation.
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
Figure 1. Normal regulation of the hypothalamic-pituitary- adrenocortical axis.1, 2 ACTH = andrenocorticotrophic hormone; CRH = corticotrophin-releasing hormone.
mortality rate in patients with Cushing’s syn- drome compared to the general population.6 Diabetes mellitus and hypertension are the most
Table 1. Signs and Symptoms of Cushing’s Syndrome5 Other
causing iatrogenic Cushing’s syndrome. Initial testing can include measurement of 24-hour
central obesity) Facial plethora
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-
Weight gain Moon facies
Irregular menses Easy bruising
Back pain Striae (especially wide
violaceous striae) Insomnia Proximal myopathy
Muscle weakness Dorsocervical fat pad
Irritability Supraclavicular fat pads Edema
Thin skin Hirsutism Female balding
mellitus Osteoporosis Renal calculi
methasone 1-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
5, 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”)
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.4 The excess cortisol overwhelms the ability of type 2 11b- 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.6 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
Before considering biochemical testing for endogenous Cushing’s syndrome, it is important to rule out exogenous glucocorticoid exposure
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 pituitary adenoma or a nonpituitary tumor with
ectopic ACTH production.
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, 11–14 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.3, 13, 15
Medical therapy for hypercortisolemia is pro- vided to patients who are unable to undergo surgery because of another illness, to patients
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-
3, 13, 16–20
date (Table 2).
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. Ketoconazole 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 11b-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 men
16, because of inhibition of testosterone synthesis. 19–21
Metyrapone blocks the production of corti- sol through inhibition of 11b-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 11b-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,
and it must often be used in combination with another drug to attain more rapid control
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-
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
able in the United States.16, 19 Etomidate, an the glucocorticoid receptor at higher doses.18
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
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-
agonists are potentially attractive agents for the ing ACTH and cortisol levels.28, 29 It has little
treatment of Cushing’s syndrome because of the potential for decreased prevalence of glu-
affinity for the mineralocorticoid receptor and estrogen receptors but is a weak antiandrogen.
cose intolerance and diabetes,6, 13, 16, 25 but Mifepristone is also a weak glucocorticoid ago-
results have been variable and few patients with Cushing’s syndrome experienced sustained improvement after receiving dopamine agonist therapy.13, 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
nist, roughly 1/250th of that of cortisol, although this weak effect is unlikely to prevent
Pharmacokinetics and Pharmacodynamics Mifepristone is readily absorbed after oral
ingestion with a bioavailability exceeding 30%.31 Time to peak plasma concentrations after oral
levels.13, 16 A newer multiligand somatostatin administration of a single dose is 1–2 hours,
analog, pasireotide (SOM230), has been demon- strated to inhibit ACTH release in human corti- cotroph cells through interaction with type 5
increasing to 1–4 hours with repeated doses. Food increases the plasma concentrations of mifepristone. Mifepristone has three active metab-
somatostatin receptors.6, 16, 26 Its use has olites, all of which have high affinity and antago-
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, possibly caused by direct inhibition of insulin and incretin hormone secretion.
Mifepristone (RU486), a derivative of the syn- thetic progestin norethindrone, was discovered in the 1980s 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
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
Significant drug–drug interactions exist because of mifepristone’s effects on several CYP
enzymes. For example, CYP3A is involved in the metabolism of mifepristone and mifepristone
Table 4. Drugs that Interact with Mifepristone Through CYP2C8/2C9 and CYP2B618
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
Drugs Metabolized by CYP2C8/2C9
Use lowest dose and
monitor closely Fluvastatin NSAIDs Warfarin Repaglinide
Not studied—use lowest dose
plasma concentration (Cmax) of simvastatin acid and a 7-fold increase in the Cmax of simvastatin, significantly increasing the risk of toxicity of this drug.18 Drugs that inhibit CYP3A can increase mifepristone levels, and a dose reduc- tion of mifepristone may be required (Table 3). Coadministration of mifepristone and CYP3A in- ducers has not been studied. Other enzymes affected by mifepristone are CYP2C8/2C9 and CYP2B6. Drugs metabolized by these pathways should be used with caution (Table 4). The Cmax of fluvastatin 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 ml/
min). There was large variability among subjects
CYP = 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
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
Table 3. Sample List of Drugs or Foods that Interact with Mifepristone Through CYP4503A18
Drugs Metabolized by CYP3A
Use alternative drug or administer
lowest dose and/or decrease frequency
Limit mifepristone to 300 mg/day
Do not use (has not
Cyclosporine Azole antifungals Rifabutin
Dihydroergotamine Protease inhibitors Phenobarbital
Ergotamine Macrolides Phenytoin
Fentanyl Mibefradil Carbamazepine
Pimozide Nefazodone St. John’s wort
Quinidine Conivaptan Rifampin
Sirolimus Caution—use lowest effective dose of mifepristone
Ciprofloxacin Grapefruit juice
CCBs = calcium channel blockers; CYP = cytochrome P450.
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-
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
lished in 1989.28, 33, 34 Six of the 10 patients patients with Cushing’s disease had improve-
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.34
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
ment in clinical signs of hypercortisolemia; levels of ACTH and cortisol increased in all four patients. The last patient treated had bilateral adrenal hyperplasia. Hypertension and signs of hypercortisolemia improved within 3 months of therapy, and hemoglobin A1c (A1C) 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- tions to therapy for diabetes, impaired glucose tolerance, depression, hyperlipidemia, or hyper- tension were not allowed, with the exception of the addition of a mineralocorticoid antagonist for the treatment of hypokalemia.
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 ti SD dose at the final study visit was 732 ti 366 mg/
In 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 point 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 A1C was 1.1% from baseline (p<0.001), and 6 of 12 patients with an A1C greater than 7% at baseline had an A1C of 6% or less by the end of the trial. Mean ti SD fasting
plasma glucose levels were reduced from 149 ti 74.7 mg/dl at baseline to 104.7 ti 37.5 mg/
dl 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 patients achieved at least a 5–mm Hg reduction in diastolic blood pressure compared to baseline (p<0.05). Two of these responders received spironolactone. When the change in blood pres- sure was evaluated in the hypertensive patients in both cohorts (diabetes plus hypertension cohort), 42.5% (17 of 40 patients) had a reduc- tion in diastolic blood pressure of at least 5 mm Hg and 27.5% were able to reduce their antihy- pertensive drug doses. However, mean systolic and diastolic blood pressures were not signifi- cantly changed.37
Individuals in both groups showed improvement in clinical manifestations of Cushing’s syndrome. Twenty-four patients lost at least 5% of baseline body weight, but 10 patients gained weight. Mean ti SD waist circumference decreased in women (ti 6.8 ti 5.8 cm, p<0.001) and men (ti 8.4 ti 5.9 cm, p<0.001). Mean percent total body fat declined by 3.6% (p<0.001). Mood, cogni- tion, and quality of life scores improved. In the patients with Cushing’s disease, magnetic reso- nance imaging demonstrated stability of the pitui- tary tumor, with the exception of one patient with an aggressive tumor.37
Limitations of this multicenter study include a relatively high dropout rate, lack of a placebo group, short study duration, and open-label design. In addition, response to therapy was lar- gely based on clinical judgment; therefore, dos- age increases, reductions, or interruptions were based on investigators’ clinical judgment. This prevented assessment of dose response to drug.
Although these studies of mifepristone dem- onstrated clinical efficacy, combination therapy with mifepristone has yet to be evaluated. Based on knowledge of other pharmacologic agents, the use of mifepristone in combination with other available drugs for the treatment of Cush- ing’s syndrome has potential. Because ketoconaz- ole is readily available and has a mechanism of action distinct from that of mifepristone, the combination of mifepristone with ketoconazole is a logical choice and may have added benefit for the treatment of Cushing’s syndrome. How- ever, because ketoconazole is a CYP3A inhibitor, it can increase mifepristone concentrations and the dose of mifepristone should not exceed
300 mg/day if used in combination with ketoco- nazole. The use of mifepristone with metyrapone would likely be limited by the fact that both drugs may worsen hypokalemia.
Safety and Tolerability
Mifepristone has a black-box warning regard- ing its ability to cause termination of pregnancy. Premenopausal women should be tested for pregnancy before being administered this drug. Mifepristone also should be used with caution when combined with drugs metabolized by CYP3A (Table 3), in patients receiving systemic corticosteroids for a transplant or immunosup- pression, in women with risk of vaginal bleeding or endometrial changes, and in patients with known prior hypersensitivity.18 Due to its anti- progesterone effects, the drug will interfere with the effectiveness of hormonal contraception. The use of nonhormonal forms of contraception should be advised.18
Serious reactions include adrenal insuffi- ciency, hypokalemia, vaginal bleeding, QT pro- longation, exacerbation of conditions treated with corticosteroids, and Pneumocystis jiroveci infection. Adrenal insufficiency occurred in 2 of the 50 subjects during a clinical trial.18 Although uncommon, it is important to monitor clinically for signs of adrenal insufficiency, because this cannot be measured biochemically while the patient is receiving mifepristone. If adrenal insufficiency occurs, treatment should be initiated promptly with potent high-dose glucocorticoids to overcome the glucocorticoid receptor–blocking effect of mifepristone and mi- fepristone should be discontinued. Because the half-life of mifepristone is long (85 hours), treat- ment with glucocorticoids should continue for at least 2 weeks. Mifepristone can be reintroduced cautiously at a lower dose after resolution of the adrenal insufficiency.18
Hypokalemia is a common adverse effect of mifepristone, occurring in 34% of patients.37 This is thought to be a result of increased bind- ing of cortisol to mineralocorticoid receptors. Because mifepristone blocks negative feedback by cortisol on ACTH-secreting pituitary adeno- mas,29 ACTH and cortisol levels can rise with mifepristone therapy, resulting in increased access by cortisol to mineralocorticoid receptors as the capacity of 11b-HSD is exceeded.1, 2 Because hypokalemia is a prominent feature of Cushing’s syndrome even in the absence of mife- pristone, it should be corrected before the initia-
tion of mifepristone, and potassium levels should be monitored closely during treatment. Consideration can be given to the addition of a mineralocorticoid receptor antagonist such as spironolactone if hypokalemia is persistent
18, 36, 38
despite potassium supplementation.
Because of the potential for activation of miner- alocorticoid receptors to worsen cardiovascular disease, mifepristone should be used with cau- tion in such patients.38
Adverse reactions occurring in at least 20% of patients include nausea, fatigue, headache, hypo- kalemia, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial hyperplasia.18 Other laboratory abnor- malities found were a reduction in high-density lipoprotein cholesterol levels and asymptomatic elevations in thyroid-stimulating hormone levels. Recommended monitoring should include mea- surement of potassium levels, clinical assessment of adrenal insufficiency, and yearly vaginal ultra- sound in women.
Dosing and Administration
Mifepristone should be administered as a once-daily oral dose with food and should be taken this way consistently to avoid changes in plasma concentrations. The starting dosage is 300 mg/day, which may be escalated by 300 mg every 2–4 weeks, not to exceed a dosage of 1200 mg/day or 20 mg/kg/day. The maximum dosage for patients with renal or mild-to-moder- ate hepatic impairment should be 600 mg/day. If used with a CYP3A inhibitor, the maximum dose should not exceed 300 mg/day.18 Dosing recommendations are based on the most recent multicenter trial data.37
Mifepristone is available as Korlym (Corcept Therapeutics Inc., Menlo Park, CA) in the Uni- ted States as of May 1, 2012, through a central distribution pharmacy. The company voluntarily offered distribution through a central distribu- tion pharmacy to ensure timely and convenient delivery of the drug to patients and to ensure that prescribers and patients are fully informed of the risks of the drug. The cost of Korlym is approximately $186 for each 300-mg pill.39 Copayment assistance and patient assistance pro- grams are available through the manufacturer, and further assistance is available through NORD (National Organization for Rare Disor- ders; 1-800-999-6673, ext. 326). Prescribers must complete a patient enrollment form and submit this to SPARK (Support Program for
Access and Reimbursement of Korlym).40 SPARK will determine insurance eligibility and assistance.
- Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s dis- ease. Best Pract Res Clin Endocrinol Metab 2009;23:607–23.
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dan B. Long-term remission rates after pituitary surgery for
Mifepristone offers an alternative mechanism of action for medical therapy of Cushing’s syn- drome. A recent clinical trial demonstrating improvement in hyperglycemia in patients with Cushing’s syndrome led to the drug’s approval by the FDA in February 2012 for use in patients with hyperglycemia secondary to Cushing’s syn- drome who have either failed surgery or are not surgical candidates. Unfortunately, outcomes other than reduction in glucose levels were less convincing. To our knowledge, no trials are comparing the efficacy of mifepristone with that of other available drugs for the treatment of Cushing’s syndrome; therefore, choosing a medi- cal therapy will remain largely a clinical judg- ment. Because mifepristone does not reduce cortisol levels, the biochemical response to the drug cannot be measured, and hypokalemia may be worsened. It also has a number of undesirable drug–drug interactions.
Because of the cost and the difficulty of moni- toring clinical effectiveness, mifepristone should be administered as a second- or third-line ther- apy in patients with Cushing’s syndrome who warrant medical management but either have failed or have a contraindication to ketoconazole or metyrapone, particularly in patients who have concomitant diabetes.
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- Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consen- sus statement. J Clin Endocrinol Metab 2008;93:2454–62.
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- Imaki T, Tsushima T, Hizuka N, et al. Postoperative plasma cortisol levels predict long-term outcome in patients with Cushing’s disease and determine which patients should be treated with pituitary irradiation after surgery. Endocr J 2001;48:53–62.
- Fleseriu M, Loriaux DL, Ludlam WH. Second-line treatment for Cushing’s disease when initial pituitary surgery is unsuc- cessful. Curr Opin Endocrinol Diabetes Obes 2007;14:323–8.
- Prevedello DM, Pouratian N, Sherman J, et al. Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg 2008;109:751–9.
- Castinetti F, Nagai M, Dufour H, et al. Gamma Knife radio- surgery is a successful adjunctive treatment in Cushing’s syn- drome. Eur J Endocrinol 2007;156:91–8.
- Liu JK, Fleseriu M, Delashaw JB. Treatment options for Cush- ing disease after unsuccessful transphenoidal surgery. Neuro- surg Focus 2007;23:1–7.
- Calao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012;366:914–24.
- Corcept Therapeutics. Korlym (mifepristone) package insert. Menlo Park, CA; 2012.
- Rizk A, Honegger J, Milian M, Baras T. Treatment options in Cushing’s disease. Clin Med Insights Oncol 2012;6:75–84.
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- Vehelst JA, Trainer PJ, Howlett TA, et al. Short and long term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1991;35:169–78.
- Kamenicky P, Droumaguet C, Salenave S, et al. Mitotain, me- tyrapone and ketoconazole combination therapy as an alterna- tive to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 2011;96: 2796–804.
- Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK. Use of parenteral propylene glycol-containing etomidate prep- aration for the long-term management of ectopic Cushing’s syndrome. J Clin Endocrinol Metab 2001;86:4104–8.
- Casulari L, Naves L, Mello P, Neto AP, Papadiu C. Nelson’s syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 2004;62:300–5.
- Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab 2006;91:4482–8.
- Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pitu- itary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicen- ter, phase II trial. J Clin Endocrinol Metab 2009;94:115–22.
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- Castinetti F, Fassnacht M, Johanssen S, et al. Merits and pit- falls of mifepristone in Cushing’s syndrome. Eur J Endocrinol 2009;160:1003–10.
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- Support Program for Access and Reimbursement of Korlym. 1-855-4Korlym. Verbal communication. May 18, 2012.
- Support Program for Access and Reimbursement of Korlym. Available from www.korlymspark.com. Accessed May 18, 2012.