Mechanism of Action
Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.
Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.
Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor (100%, 61%, 48%, and 45%, respectively) than either dexamethasone (23%) or cortisol (9%).
Following oral administration, time to peak plasma concentrations of mifepristone occurred between 1 and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of Korlym in healthy volunteers. Mean plasma concentrations of three active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, and the combined concentrations of the metabolites exceed that of the parent mifepristone. Exposure to mifepristone is substantially less than dose proportional. Time to steady state is within 2 weeks, and the mean (SD) half-life of the parent mifepristone was 85 (61) hours following multiple doses of 600 mg/day of Korlym.
Studies evaluating the effects of food on the pharmacokinetics of Korlym demonstrate a significant increase in plasma levels of mifepristone when dosed with food. To achieve consistent plasma drug concentrations, patients should be instructed to always take their medication with meals.
Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and approaches saturation at doses of 100 mg (2.5 μM) or more. Mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (CNS). As determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. Binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations.
Cytochrome P450 3A4 (CYP3A4) has been shown to be involved in mifepristone metabolism in human liver microsomes. Two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated).
Elimination and Excretion
Excretion is primarily (approximately 90%) via the fecal route.
The pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min, but not on dialysis) was evaluated following multiple doses of 1200 mg Korlym for 7 days. Mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (CrCL ≥ 90 mL/min). There was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.21 [0.71-2.06]; metabolite 1: 1.43 [0.84-2.44]; metabolite 2: 1.18 [0.64-2.17] and metabolite 3: 1.19 [0.71-1.99]). No change in the initial dose of Korlym is needed for renal impairment; the maximum dose should not exceed 600 mg per day.
The pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (Child-Pugh Class B) was evaluated in a single- and multiple-dose study (600 mg for 7 days). The pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. There was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.02 [0.59-1.76]; metabolite 1: 0.95 [0.52-1.71]; metabolite 2: 1.37 [0.71-2.62] and metabolite 3: 0.62 [0.33-1.16]). Due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. The pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. Korlym is not recommended in patients with severe hepatic disease.
In Vitro Assessment of Drug Interactions
In vitro studies indicate a potential for CYP-mediated drug interactions by mifepristone and/or its metabolites with substrates of CYP2A6, CYP2C8/2C9, CYP2C19, CYP3A4, CYP1A2, CYP2B6, CYP2D6, and CYP2E1. In vitro studies also indicated an interaction potential for drug transport mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro studies indicate mifepristone metabolism is mediated by CYP3A, and that mifepristone also inhibits and induces CYP3A.
In Vivo Assessment of Drug Interactions (see Table 2)
Table 2: Summary Table of Korlym Drug-Drug Interaction
|Dosing of Mifepristone||Coadministered Drug||Dosing of Coadministered Drug||Geometric Mean Ratio (analyte ratio with/without drug coadministration)|
|Effect of Korlym on Coadministered Drug|
|Contraindicated with mifepristone [See CONTRAINDICATIONS]|
|1200 mg once daily for 10 days||simvastatin1||80 mg single dose||simvastatin acid simvastatin||15.7||18.2|
|Use lowest dose of coadministered drug, based on clinical experience and/or use of therapeutic drug monitoring|
|1200 mg once daily for 10 days||alprazolam2||1 mg single dose||alprazolam||1.8||0.81|
|1200 mg once daily for 7 days||fluvastatin3||40 mg single dose||fluvastatin||3.57||1.76|
|1200 mg once daily for 10 days||digoxin4||0.125 mg once daily||digoxin||1.4||1.64|
|Effect of Coadministered Drug on Korlym|
|No dosing adjustment required|
|300 mg once daily for 14 days||cimetidine5||800 mg once daily||mifepristone||0.85*||0.75|
|*No effect = 90% CI within range 0.80 – 1.25
1 Simvastatin 40 mg dose used as reference for the comparison. Result could be representative of other oral drugs with CYP3A metabolism and high first pass effect: cyclosporine, midazolam, triazolam, pimozide, sildenafil, sirolimus, and tacrolimus
2 Result could be representative of other oral drugs with CYP3A metabolism and low first pass effect. Clinical significance of any interaction will depend on the therapeutic margin of the drug.
3 Result could be representative of other oral drugs with CYP2C8/C9 metabolism
4 Plasma digoxin concentration should be measured after 1 to 2 weeks of concomitant use and following usual clinical practice at appropriate intervals thereafter.
5 Result could be representative of other mild inhibitors of CYP3A 15
An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of Korlym in the treatment of endogenous Cushing's syndrome. The study enrolled 50 subjects with clinical and biochemical evidence of hypercortisolemia despite prior surgical treatment and radiotherapy. The reasons for medical treatment were failed surgery, recurrence of disease, and poor medical candidate for surgery. Forty-three patients (86%) had Cushing's disease, four patients (8%) had ectopic ACTH secretion, and three (6%) had adrenal carcinoma. Baseline characteristics included: mean age of 45 years (range 26 to 71), mean BMI of 36 kg/m² (range 24 to 66), mean weight 100 kg (range 61 to 199), and mean waist circumference was 119 cm (range 89 to 178); 70% were female; 84% were white and 16% were black or African American. Baseline mean urinary free cortisol level was 365 μg per 24 hr.
Patients belonged to one of two cohorts: a “diabetes” cohort (29 patients, 26 with type 2 diabetes and 3 with glucose intolerance), and a “hypertension” cohort (21 patients). Efficacy was evaluated separately in the two cohorts. Korlym treatment was started in all patients at a dose of 300 mg once a day. The study protocol allowed an increase in dose to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks to a maximum of 900 mg per day for patients < 60 kg, or 1200 mg per day for patients > 60 kg, based on clinical tolerance and clinical response.
Results in the diabetes cohort
Patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the clinical study. Anti-diabetic medications were allowed but had to be kept stable during the trial and patients had to be on stable anti-diabetic regimens prior to enrollment. The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a patient who had a ≥ 25% reduction from baseline in glucose AUC. The primary efficacy analysis was conducted in the modified intent-to-treat- population (n=25) defined as all patients who received a minimum of 30 days on Korlym. Fifteen of 25 patients (60%) were treatment responders (95% CI: 39%,78%).
Mean HbA1C was 7.4% in the 24 patients with HbA1c values at baseline and Week 24. For these 24 patients mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7) from baseline to the end of the trial. Fourteen of 24 patients had above normal HbA1c levels at baseline, ranging between 6.7% and 10.4%; all of these patients had reductions in HbA1c by the end of the study (range -0.4 to -4.4%) and eight of 14 patients (57%) normalized HbA1c levels at trial end. Antidiabetic medications were reduced in 7 of the 15 DM subjects taking antidiabetic medication and remained constant in the others.
Results in the hypertension cohort
Signs and symptoms of Cushing's syndrome in both cohorts
Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight. Because of the variability in clinical presentation and variability of response in this open label trial, it is uncertain whether these changes could be ascribed to the effects of Korlym.
Last reviewed on RxList: 2/23/2012
This monograph has been modified to include the generic and brand name in many instances.
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