Mifepristone for Management of Cushing's Syndrome

Abstract

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 hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, 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 control 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, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency 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, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome.

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

“…A 4 days subchronic antagonism of GR was sufficient to have fully beneficial outcomes on memory impairment, corroborating a recent study in older 3xTg mice with more advanced AD pathology, which employed a chronic infusion of GR antagonist for 3 weeks (Baglietto-Vargas et al, 2013). This shorter daily treatment holds the advantage of minimizing the possible side effects of prolonged GR blockade (Morgan and Laufgraben, 2013).…”

The Treatment of Cushing's Disease

“…Glucocorticoid antagonism is rapidly effective in controlling hypercortisolism, so it can play a role in the management of CD, especially when the presence of severe disease or concomitant conditions requires a rapid control of cortisol excess. Mifepristone is the first and only glucocorticoid receptor antagonist available, and it was approved by the FDA in the United States in February 2012 for the treatment of hyperglycemia in patients with endogenous CS associated with diabetes mellitus or glucose intolerance who are not candidates for surgery or who have not responded to prior surgery (741)(742)(743)(744)(745)(746). Experimental data are only presently available regarding different potential drugs belonging to this category.…”

“…Mifepristone is administered orally, and it has a rapid onset of action (1-4 h) and a long half-life (24 -90 h), which permits once daily administration at dosages ranging from 300 to 1200 mg/d (752). Because the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, these parameters cannot be considered in the evaluation of drug efficacy or to monitor disease control, which needs to be based on the evaluation of clinical parameters (746). In addition, the cortisol excess, which is further enhanced by glucocorticoid receptor blockade, might activate the mineralocorticoid receptor (753), potentially resulting in an increase in blood pressure, hypokalemia, edema, and alkalosis, which requires the use of high-dose antialdosterone treatment for prevention and/or control (741).…”

Mifepristone Treatment of Cushing’s Syndrome in a Pediatric Patient

“…On the basis of this study, mifepristone was recently approved by the US Food and Drug Administration (FDA) for adults with endogenous CS and hyperglycemia. 5,8,9 Here we report the first use of mifepristone in a pediatric patient with CS. We found that mifepristone successfully mitigated the comorbidities of CS, including insulin resistance, hypertension, and myopathy.…”

“…However, it is also a competitive antagonist of glucocorticoid action at the glucocorticoid receptor (GR), prompting its development as a treatment of CS. [4][5][6][7] In a recent trial, the administration of mifepristone resulted in improvement in hypertension and hyperglycemia control in adults with CS. On the basis of this study, mifepristone was recently approved by the US Food and Drug Administration (FDA) for adults with endogenous CS and hyperglycemia.…”