Concomitant administration of CYP3a4 inducers and mifepristone

Abstract

Safe and effective methods for treating a subject suffering from cortisol excess of and in need of concomitant administration of mifepristone along with a CYP3A4 inducer are disclosed herein. The CYP3A4 inducer may be, for example, mitotane, rifampin (also known as rifampicin), rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, or St. John's wort. In embodiments, the CYP3A4 inducer is a strong CYP3A4 inducer. In embodiments, the CYP3A4 inducer is a moderate CYP3A4 inducer. In embodiments, the CYP3A4 inducer may be any CYP3A4 inducer. Mifepristone may be orally administered. Mifepristone may be administered with food.

Description

PATENTAttorney Docket No. 085178- 1519989-01891 OWOConcomitant Administration of CYP3A4 Inducers and MifepristoneBACKGROUND

[0001] c ortisol is a glucocorticoid (GC) hormone that has broad effects on many bodily systems, including the immune system. Cortisol acts by binding to glucocorticoid receptor (GR) type II, also referred to as the cortisol receptor. GR binding to cortisol results in agonism of the receptor, transport of the corti sol -bound receptor complex into the cell nucleus, and interaction of that complex with nuclear DNA and DNA-related proteins to affect translation of genetic message and thereby to alter a wide range of cellular processes. GR is expressed in most human cells and is particularly abundant m immune cells.

[0002] The adrenal glands are the natural source of cortisol. Cortisol is produced and secreted by the adrenal glands in response to adrenocorticotrophic hormone (ACTH) which is secreted by the pituitary gland (in response to corticotrophin releasing hormone (CRH) produced in the hypothalamus). The levels of cortisol in the blood change during the day, with the highest levels in the morning and the lowest levels at night. The normal range for morning serum cortisol is 10- 20 ug / dL or 276-552 nM. High morning cortisol prepares the body for the transition from night to day, increasing wakefulness, increasing blood glucose levels, and affecting blood pressure.Cortisol levels may be measured in blood (e.g., serum, plasm, or whole blood), in urine (e.g., 24- hour urinary’ cortisol measurement), saliva (e.g., late-night salivary' cortisol, when the cortisol levels are typically lowest), and other bodily fluids (e.g., tears and sweat). Cortisol may also be measured after a dexamethasone suppression test, in which cortisol provides a measure of the response of the hypothalamic-pituitary-adrenal axis to externally administered glucocorticoids such as dexamethasone.

[0003] However, disorders of cortisol, including altered circadian rhythm and including excess levels of cortisol can have significant health effects. Cortisol excess may be termed “hypercortisolemia” or “hypercortisolism”. Cortisol excess is related to, and causes, many disorders, including Cushing’s syndrome, hyperglycemia, hypertension, hormonal disorders, hypercoagulopathy, psychological disorders, and other diseases and disorders. Excess cortisol imay be caused by adrenal abnormalities (e.g., an adrenal tumor), or by excess ACTH release from the pituitary gland (or in some cases, by ACTH-secreting tumors) acting on the adrenal glands to produce the excess cortisol. Hypercortisolism can affect every organ system and can be lethal if not treated effectively.

[0004] When excess pituitary ACTH release causes the excess cortisol, the disorder is termed “Cushing’s Disease”. Such excess pituitary ACTH release is typically caused by a pituitary tumor. Medical treatment to reduce cortisol production, or to block the effects of cortisol (e.g., mifepristone (prescribed as KORLYM®)) is often administered, particularly when symptoms persist following surgery. Drugs which modulate the effects of cortisol are termed glucocorticoid receptor modulators (GRMs); GRMs which reduce GR activation by cortisol (reduce the response to cortisol) are termed glucocorticoid receptor antagonists (GRAs).

[0005] Patients suffering from other disorders may also exhibit excess cortisol, and excess cortisol may be a cause of such disorders. For example, patients suffering from adrenocortical cancer (ACC) may exhibit cortisol abnormalities such as excess cortisol, or altered cortisol circadian rhythm. Patients suffering from psychotic major depression typically exhibit excess cortisol. Thus, cortisol excess may cause a disorder (e.g., Cushing’s syndrome), or may be associated with a disorder as a symptom, or as a possible characteristic of a disorder,

[0006] Thus, since excess cortisol may be the cause of, or may occur along with, many disorders, treatment of which disorders may require the administration of more than one medical therapy, co-administration of two or more drugs may be required during treatment of patients suffering from excess cortisol. Enzymes in the liver and other organs play critical roles in metabolizing administered drugs. However, when two or more drugs are administered at the same time, or are present in the body at the same time, even if administered at different times (such concurrent presence of two or more drugs in the body is termed “concomitant administration”), the presence of one drug may interfere with, or alter, the metabolism of another drug also present in the body.

[0007] Many enzymes are involved in the metabolism of naturally occurring and exogenously administered compounds, including cytochrome P450 enzymes, which are encoded by CYP genes. For example, CYP3A enzymes play important roles in the synthesis of steroid hormones such as cortisol. In addition, such enzymes may also metabolize drugs that may be administeredto subjects. For example, cytochrome P450 3A4 (CYP3A4) has been shown to be involved in mifepristone metabolism in human liver microsomes.

[0008] Thus the plasma levels of a drug are affected not only by the amount of drug that has been administered, but may also be affected by the amount (and rate) of its metabolism. Drugs that increase the levels of, or that increase the activity of, metabolic enzymes such as CYP3A4 can significantly reduce the plasma levels of other drugs which are administered or are present at times where there are sufficient levels of both drugs in a subject. Such drugs that increase the levels of, or that increase the activity’ of, metabolic enzymes are said to be inducers of that enzyme; enzyme inducers may lower the levels of drugs that are substrates of the enzyme whose level or activity has been induced.

[0009] Drugs that increase the levels of, or that increase the activity’ of, CYP3A4 enzymes are termed CYP3A4 inducers. For example, the following drugs induce CYP3A4 and are CYP3A4 inducers: mitotane, rifampin (also known as rifampicin), rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort. A strong CYP3A4 inducer is a drug that decreases the AUC of sensitive substrates of CYP3A4 by >80 percent. A moderate inducer is a drug that decreases the AUC of sensitive substrates of CYP3A4 by >50 to <80 percent. (See the FDA publication “Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers” available on the U.S. Food and Drug Administration web site FDA.gov, page “drug- interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and- inducers”, accessed on February 27, 2024. ) Strong inducers of CYP3A4 include carbamazepine, phenytoin, and rifampin.

[0010] Due to concerns about increased metabolism of mifepristone following induction of increased CYP3A4 levels or activity, the U.S. Food and Drug Administration (FDA) included “Drug Interactions” warnings in the label for KORLYM® (a mifepristone tablet): “CYP3A inducers: Do not use KORLYM with CYP3A inducers” and “Avoid coadministration of KORLYM and CYP3 A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort.” (KORLYM FDA Label).

[0011] There is need in the art to provide safe and effective methods for the treatment of disorders of excess cortisol, including Cushing’s syndrome and Cushing’s Disease, in which two or more drugs are concomitantly administered to a patient in need of treatment. For example, there is need in the art to provide safe and effective methods of administering GRMs such asmifepristone along with other drugs, inciuding CYP3A inducer drugs, for the treatment of disorders caused by, or associated with, excess cortisol. Accordingly, improved methods of treatment allowing the administration of GRM drugs along with CYP3A inducers are desired.

[0012] Such improved methods, providing safe and effective methods for concomitant administration of GRMs along with other drugs in the treatment of patients in need of treatment for cortisol excess, and of patients in need of treatment for disorders associated with cortisol excess, are disclosed in the following.SUMMARY

[0013] Disorders of cortisol excess include Cushing’s syndrome, Cushing’s Disease, cortisol excess due to adrenal carcinoma or other carcinoma, and other disorders. Such disorders, or their symptoms, may often be treated by administration of a GRM such as mifepristone. Patients suffering from disorders related to excess cortisol are often also in need of other medication, e.g., to treat hypertension, or a liver disorder, or inflammation, or other disorder, whether related to cortisol excess or whether the patient suffers from another disorder at the same time that they suffer from cortisol excess. In many cases, such other medication may be a CYP3A4 inducer.

[0014] Thus, patients suffering from cortisol excess may be administered mifepristone, and may also receive another medication, which may be a CYP3A4 inducer. However, since mifepristone is metabolized by CYP3A4 enzymes, concomitant administration of an effective dose of mifepristone along with a CYP3 A4 inducer would be expected to result in lower, and possibly ineffective, levels of mifepristone due to increased metabolism of mifepristone by (induced) CYP3A4 enzymes as compared to mifepristone levels obtained with that effective dose of mifepristone in the absence of a CYP3A4 inducer. In such a case, concomitant administration of mifepristone with a CYP3 A4 inducer would be expected to reduce or eliminate the therapeutic effects of mifepristone, and thus be detrimental to the patient.

[0015] Surprisingly, Applicant discloses herein safe and effective methods of concomitant administration of mifepristone along with a CYP3A4 inducer. The CYP3A4 inducer may be, for example, mitotane, rifampin (also known as rifampicin), rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, or St. John’s wort In embodiments, the CYP3A4 inducer is a strong CYP3A4 inducer. In embodiments, the CYP3A4 inducer is a moderate CYP3A4 inducer. In embodiments, the CYP3A4 inducer may be any CYP3A4 inducer.

[0016] Accordingly, Applicant discloses herein novel methods for safely treating patients who are in need of concomitant treatment with mifepristone and with a CYP3A4 inducer, comprising: administering an original dose of mifepristone for at least 7 days; then administering an effective dose of said CYP3A4 inducer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and wherein said increased dose of mifepristone is less than about 2500 or 3000 milligrams (mg) of mifepristone; wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said CYP3A4 inducer, whereby the patient is safely treated with both mifepristone and a CYP3A4 inducer. In embodiments of the methods disclosed herein, the increased dose of mifepristone is about two times, or about three times, the original dose of mifepristone, wherein the increased dose of mifepristone is less than about 2500 or 3000 milligrams (mg) of mifepristone.

[0017] In embodiments, the patient is a Cushing’s Syndrome patient who is in need of concomitant treatment with mifepristone and with a CYP3A4 inducer. In embodiments, the patient is a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer, and in need of treatment for hypertension. In embodiments, the patient is a patient suffering from Cushing’s syndrome and from hypertension, wherein said hypertension is treatable byadministration of an antihypertensive medication, wherein said antihypertensive medication is a CYP3 A4 inducer. In embodiments, the patient is a Cushing’s Syndrome patient who is in need of treatment with a CYP3A4 inducer and is at risk for increasing liver enzyme levels in the blood due to administration of said CYP3 A4 inducer.

[0018] In embodiments, Applicants disclose methods to improve the efficacy of antihypertensive medications and to safely treat a patient suffering from adrenocortical cancer, from hypertension, and from Cushing’s syndrome, said patient receiving mitotane, wherein said hypertension is treatable by administration of an antihypertensive medication, wherein said antihypertensive medication is metabolized by CYP3A4, the method comprising: administering an original dose of mifepristone for at least 7 days to said patient suffering from adrenocortical cancer, from hypertension, and from Cushing’s syndrome, said patient receiving mitotane; thenadministering an effective dose of said antihypertensive medication that is metabolized by CYP3A4; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said onginai dose of mifepristone, and said increased dose is less than about 2500 or 3000 mg of mifepristone; wherein said co-admini strati on of said increased dose of mifepristone with said antihypertensive medication that is metabolized by CYP3A4 is effective to improve the efficacy of said hypertensive medication in the patient as compared to the effectiveness of said hypertensive medication in the absence of pre-treatment with mifepristone. In embodiments, said increased dose of mifepristone is about two times, or about three times, the original mifepristone dose, and less than about 2500 or 3000 mg of mifepristone.

[0019] In embodiments, mifepristone is orally administered. In embodiments, mifepristone is administered with food.

[0020] In embodiments, an effective original amount of mifepristone is a daily dose of about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 milligrams per day (mg / day). In embodiments, an effective increased amount of mifepristone is a daily dose of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg / day.

[0021] In embodiments, the GRM is administered once per day, in other embodiments, the GRM is administered twice, or three times, per day, where the total daily dose is calculated byadding up each of the 2 or 3 doses administered in a single day. Mifepristone may be administered concomitantly with a CYP3A4 inducer for as long as such concomitant administration is indicated for the treatment of the patient.

[0022] The novel methods for concomitant administration of mifepristone disclosed herein are believed to provide safe and effective methods for treating patients suffering from cortisol excess (e.g. Cushing’s syndrome and other disorders characterized by excess blood levels of cortisol) who are in need of treatment with mifepristone along with a CYP3A4 inducer.BRIEF DESCRIPTION OF THE DRAWING

[0023] The Figure shows geometric mean plasma concentrations of mifepristone after oral administration of a single 1500 mg dose of mifepristone before and after dosing for 14 days with rifampin 600 mg QD (once per day) to healthy human volunteers. The graph on the left of the figure is a plot with linear axes. The graph on the right of the figure is a plot with a semi- logarithmic vertical axis and a linear horizontal axis. The vertical axes show mifepristone plasma concentrations in nanograms per milliliter (ng / mL). The horizontal axes show time in hours.DETAILED DESCRIPTION

[0024] The simultaneous, or nearly simultaneous (e.g., concomitant) presence of two drugs in a subject may alter the effects of one or the other, or both, drugs. Such alterations are termed drug-drug interactions. For example, the required dose of a drug is often strongly affected by the amount and rate of its enzymatic degradation in the body (e.g., by liver or kidney action). However, the presence of a second drug in the body, e.g., one which is also being acted upon by enzymatic action (e.g., in the liver and / or kidney), can have significant effects on the amount and rate of degradation of the first drug, and can increase or decrease the amount of the first drug that remains in the body at a given time beyond the amount that would have been present at that time in the absence of the second drug. For example, a second drug that increases the level or activity of a metabolic enzyme may decrease the levels of a first drug that is metabolized by that metabolic enzyme as compared to the levels of the first drug that would be obtained in the absence of the second drug. Thus, the presence of a second drug can often alter the effective dose of the first drug. Where the first drug has less or no effect at lower dosages, such a decrease in effective dose of the first drug may reduce or obviate the effectiveness of the first drug due to the presence of the second drug.

[0025] Mifepristone is metabolized by CYP3A4 enzymes. CYP3A4 enzymes are induced by CYP3A4 inducers, including mitotane, rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St John's wort. Concomitant administration of mifepristone with a CYP3A4 inducer would be expected to reduce the plasma levels of mifepristone resulting from a first dose of mifepristone below that obtained by such a first dose administered in the absence of a CYP3A4 inducer. Such reduction would be expected to reduce or eliminate the therapeutic effects of mifepristone.

[0026] The present methods provide improved methods of treating Cushing’s syndrome, Cushing’s Disease, hypertension in a patient suffering from cortisol excess (e.g., suffering from Cushing’s syndrome, Cushing’s Disease, adrenocortical cancer, or other disorder that may cause cortisol excess), or other disorder related to cortisol excess or to cancer, including in patients suffering from Cushing’s syndrome and also suffering from other disorders (e.g., a bacterial infection, meningitis, tuberculosis, inflammation, or other disorder).

[0027] Accordingly, Applicant discloses methods for safely treating a Cushing’s Syndrome patient who is in need of concomitant treatment with mifepristone and with a CYP3A4 inducer, comprising: administering an original dose of mifepristone for at least 7 days; then administering an effective dose of said CYP3A4 inducer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and wherein said increased dose of mifepristone is less than about 2500 or 3000 milligrams (mg) of mifepristone; wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said CYP3A4 inducer, whereby the patient is safely treated with both mifepristone and a CYP3A4 inducer.

[0028] In embodiments, the need for treatment with a CYP3A4 inducer may comprise need to treat an adrenal tumor, where the effective dose of said CYP3A4 inducer is effective to treat said adrenal tumor in the patient. In embodiments, the need for treatment with a CYP3 A4 inducer may comprise the need to treat hypertension, where the effective dose of said CYP3A4 inducer is effective to treat said hypertension in the patient.

[0029] Accordingly, Applicant discloses methods to safely control hypertension in a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer, administering an original dose of mifepristone for at least 7 days to said patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer; then administering an effective dose of a CYP3A4 inducer useful in treating hypertension in said patient suffering from adrenocortical cancer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and said increased dose is less than about 2500 or 3000 mg of mifepristone;wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said CYP3A4 inducer, whereby the patient is safely treated with both mifepristone and a CYP3A4 inducer effective to aid in the control of hypertension in the patient.

[0030] Accordingly, Applicant discloses methods to safely treat a patient suffering from Cushing’s syndrome and from hypertension, wherein said hypertension is treatable by administration of an antihypertensive medication, wherein said antihypertensive medication is a CYP3A4 inducer, the method comprising: administering an original dose of mifepristone for at least 7 days; then administering an effective dose of said antihypertensive medication that is a CYP3A4 inducer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and said increased dose is less than about 2500 or 3000 mg of mifepristone; wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said antihypertensive medication that is a CYP3A-4 inducer.

[0031] Accordingly, Applicant discloses methods for safely treating a Cushing’s Syndrome patient who is in need of treatment with a CYP3A4 inducer and is at risk for increasing liver enzyme levels in the blood due to administration of said CYP3A4 inducer: administering an original dose of mifepristone for at least 7 days; then administering an effective dose of said CYP3A4 inducer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and said increased dose is less than about 2500 or 3000 mg of mifepristone; wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said CYP3A4 inducer, wherein, during said co-administration of mifepristone with said CYP3A4 inducer the liver enzyme levels in the blood of the patient remain lower than the liver enzyme levels expected in a patient receiving said CYP3A4 inducer in the absence of mifepristone pre-treatment, whereby the patient is safely treated with both mifepristone and a CYP3A4 inducer.In embodiments, said increased dose of mifepristone is about two times, or about three times, the original mifepristone dose, and less than about 2500 or 3000 milligrams (nig) of mifepristone.

[0032] Accordingly, Applicant discloses methods to safely improve the efficacy of antihypertensive medications and to safely treat a patient suffering from adrenocortical cancer, from hypertension, and from Cushing’s syndrome, said patient receiving mitotane, wherein said hypertension is treatable by administration of an antihypertensive medication, wherein said antihypertensive medication is metabolized by CYP3A4, the method comprising: administering an original dose of mifepristone for at least 7 days to said patient suffering from adrenocortical cancer, from hypertension, and from Cushing’s syndrome, said patient receiving mitotane; then administering an effective dose of said antihypertensive medication that is metabolized by CYP3A4; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and said increased dose is less than about 2500 or 3000 mg of mifepristone; wherein said co-admimstration of said increased dose of mifepristone with said antihypertensive medication that is metabolized by CYP3A4 is effective to improve the efficacy of said hypertensive medication in the patient as compared to the effectiveness of said hypertensive medication in the absence of pre-treatment with mifepristone. In embodiments, the antihypertensive medication that is metabolized by CYP3A4 is selected from amlodipine, bisoprolol, carvedilol, diltiazem, eplerenone, felodipine, indapamide, isradipine, nifedipine, nimodipine, nisoldipine, and nitrendipine.

[0033] In embodiments, the need for treatment with a CYP3 A4 inducer may comprise the need to treat a bacterial infection, where the effective dose of said CYP3A4 inducer is effective to treat said bacterial infection in the patient. In embodiments, the need for treatment with aCYP3 A4 inducer may comprise the need to treat tuberculosis, where the effective dose of said CYP3A4 inducer is effective to treat said tuberculosis in the patient. In embodiments, the need for treatment with a CYP3A4 inducer may comprise a need to treat meningitis, where said effective dose of said CYP3A4 inducer is effective to treat said meningitis in the patient.

[0034] The methods disclosed herein are believed to be effective for safely treating a patient concomitantly receive mifepristone and a CYP3A4 inducer, wherein the mifepristone dose iseffective to aid in the treatment of Cushing’s Syndrome or other disorder without reducing cortisol levels to unsafe levels. The methods disclosed herein are believed to be effective for safely treating a patient concomitantly receive mifepristone and a CYP3A4 inducer, whereby the patient is not exposed to increased risk of adrenal insufficiency.

[0035] In embodiments, the CYP3A4 inducer may be a medication for treating cancer, a medication for treating hypertension, a medication for treating hypercoagulation, a medication for treating a bacterial infection, a medication for treating tuberculosis, a medication for treating meningitis, an anti-inflammatory medication (e.g., a glucocorticoid), or other medication.

[0036] In embodiments of any and all of the methods disclosed herein for safely treating a patient who is in need of concomitant treatment with mifepristone and with a CYP3A4 inducer, said increased dose of mifepristone is about two times, or about three times, the original mifepristone dose, and is less than about 2500 or 3000 mg of mifepristone. In embodiments of any and all of the methods disclosed herein, the CYP3A4 inducer may be selected from mitotane, rifampin, rifabutin, rifapentm, phenobarbital, phenytoin, carbamazepine, and St. John's wort,

[0037] In embodiments of any and all of the methods disclosed herein, the original dose of mifepristone may be selected from the group consisting of about 50 mg, 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg. In embodiments, the original dose of mifepristone is selected from the group consisting of about 300 mg, about 600 mg, about 900 mg, about 1200 mg, and about 1500 mg. In embodiments of any and all of the methods disclosed herein, the increased dose of mifepristone may be selected from the group consisting of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, and about 3000 mg.

[0038] In embodiments, the dose of the CYP3A4 inducer is a typical dose for the CYP3A4 inducer. For example, where the CYP3A4 inducer is rifampin, the CYP3A4 inducer dose may be between about 100 milligrams (mg) to about 1200 mg, and may be administered orally once perday, or in divided doses twice, or more times per day; rifampin doses, for example, may be seiected from the group consisting of about 300 mg, about 600 mg, and about 900 mg per day. For example, where the CYP3A4 inducer is mitotane, the daily dose may be between about 1 gram (gm) to about 10 g, per day, and may be administered orally once per day, or in divided doses twice, or more times per day; mitotane doses, for example, may be selected from the group consisting of about 2 g, about 4 g, and about 6 g per day. For example, where the CYP3A4 inducer is rifabutin, the CYP3A4 inducer dose may be between about 300 mg to about 1200 mg per day, and may be administered orally once per day, or in divided doses twice, or more times per day; rifabutin doses, for example, may be selected from the group consisting of about 150 mg twice per day; about 300 nig once per day; about 600 mg per day in one or more doses; and about 900 mg per day in one or more doses. For example, where the CYP3A4 inducer is rifapentine, the CYP3A4 inducer dose may be between about 300 mg to about 1200 mg per week, and may be administered orally once per week, or in divided doses twice, or more times per week; rifapentine doses, for example, may be selected from the group consisting of about 200 mg twice per week; about 400 mg twice per week; about 600 mg twice per week; and about 900 mg once per week. For example, where the CYP3A4 inducer is phenobarb itol, the CYP3A 4 inducer dose may be between about 50 mg to about 400 mg per day, and may be administered orally once per day, or in divided doses twice, or more times per day; phenobarbitol doses, for example, may be selected from the group consisting of about 50 mg once per day; about 65 mg once per day, about 200 mg once per day; and about 300 mg once per day. For example, where the CYP3A4 inducer is phenytoin, the CYP3A4 inducer dose may be between about 50 mg to about 500 mg per day, and may be administered orally once per day, or in divided doses twice, or more times per day; phenytoin doses, for example, may be selected from the group consisting of about 100 mg once, twice, or thrice per day; about 300 mg once per day; about 300 mg once per day; and about 500 mg once per day. For example, where the CYP3A4 inducer is carbamazepine, the CYP3A4 inducer dose may be between about 50 mg to about 800 mg per day, and may be administered orally once per day, or in divided doses twice, or more times per day; carbamazepine doses, for example, may be selected from the group consisting of about 100 mg once, twice, thrice, or four times per day; about 200 mg once or twice per day; about 400 mg once per day; and about 800 mg once per day. For example, where the CYP3A4 inducer is St. John's wort, the CYP3A4 inducer dose may be between about 300 mg to about 1200 mg per day,and may be administered orally once per day, or in divided doses twice, or more times per day; St. John's wort doses, for example, may be selected from the group consisting of about 300 mg once, twice, thrice, or four times per day; about 300 mg once, twice, or thrice per day; about 450 mg once or twice per day; and about 900 mg once per day.DEFINITIONS

[0039] As used herein, the term “patient” refers to a human or other mammal that is or will be receiving, or has received, medical care for a disease or condition.

[0040] As used herein, the term “tumor” and the term “cancer” are used interchangeably and both refer to an abnormal growth of tissue that results from excessive cell division

[0041] As used herein, the terms “adrenocortical cancer”, “adrenocortical carcinoma”, and the acronym “ACC” are used interchangeably to refer to adrenal gland adrenocarcinomas. Approximately half of patients suffering from ACC have systemic cortisol excess.

[0042] As used herein, the term “about”, e.g., as used in the phrase “about X” where X is a numerical value, is used to indicate a range of ±10% of the named value of X.

[0043] As used herein, the term “substantially”, e.g., as used in the phrase “X is substantially the same as Y” refers to a value of X that is within about 30%, or within about 25%, or within about 20%, or within about 15%, or within about 10% of the value of the term Y.

[0044] As used herein, the terms “per cent”, “%” and “weight percent” when applied to a dosage administered to a subject, all refer to a percentage taken by comparing the weight of a first dose to that of a second dose, and multiplying the resulting decimal fraction by 100. Thus, for example, where an original mifepristone dose is 1200 milligrams (mg), a dose that is increased by 50% is a dose of 1800 mg mifepristone; and where an original mifepristone dose is 600 milligrams (mg), a dose that is increased by 50% is a dose of 900 mg mifepristone; and so forth,

[0045] For example, w'here an original mifepristone dose is 600 mg, an increased dose that is increased to about twice the original dose is increased to 1200 mg (an increase of 100%), and an original dose of 500 mg dose of mifepristone that is increased to about three times the original dose is increased to a dose of 1500 mg mifepristone (an increase of 200%); and so forth.

[0046] As used herein, the phrases “greater than x by at least”, “greater than x by at least about”, and the like refer to amounts equal to and greater than the x, where x is a number. For example, the phrase “greater than the original dosage by at least 50%” refers to dosage amounts thatinclude 50% more than the original dosage as well as other percentages (e.g., 51%, 52%, etc.) more than the original dosage amount.

[0047] The term “measuring the level,” in the context of cortisol, or mifepristone, or a CYP3A4 inducer, or other analyte, refers determining, detecting, or quantitating the amount, level, or concentration of, for example, cortisol, mifepristone, a CYP3A4 inducer, or other analyte in a sample obtained from a subject. The sample may be, e.g., a blood sample, a saliva sample, a urine sample, or other sample obtained from the patient. A level may be measured from a fraction of a sample. For example, a level (e.g., of cortisol, of mifepristone, or of a CYP3A4 inducer) may be measured in the plasma fraction of a blood sample; may be measured in a serum fraction of a blood sample; or, in embodiments, may be measured in whole blood.

[0048] The term “glucocorticoid” (“GC”) or “glucocorticosteroid” refers to a steroid hormone that binds to a glucocorticoid receptor. Glucocorticosteroids are typically characterized by having 21 carbon atoms, an a,P~unsaturated ketone in ring A, and an a-ketol group attached to ring D. Glucocorticoids used in clinical practice (e.g., as anti-inflammatory agents) include dexamethasone, prednisone, prednisolone, methylprednisone, triamcinolone, cortisone, betamethasone, beclomethasone, and budesonide.

[0049] The term “cortisol” refers to the naturally occurring glucocorticoid hormone (also known as hydrocortisone) that is produced by the zona fasciculata of the adrenal gland. Cortisol has the structure:The term ‘"total cortisol” refers to cortisol that is bound to cortisol-binding globulin (CBG or transcortin) and free cortisol (cortisol that is not bound to CBG). The term “free cortisol” refers to cortisol that is not bound to cortisol-binding globulin (CBG or transcortin). As used herein, the term “cortisol” refers to total cortisol, free cortisol, and / or cortisol bound of CBG.

[0050] The term “glucocorticoid receptor modulator” (GRM) refers to any compound which modulates GC binding to GR, or which modulates any biological response associated with thebinding of GRto an agonist. For example, a GRM that acts as an agonist, such as the GC dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK). A GRM that acts as an antagonist, such as mifepristone, decreases the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0051] “Glucocorticoid receptor antagonist” (GRA) refers to any compound which inhibits GC binding to GR, or which inhibits any biological response associated with the binding of GR to an agonist. Accordingly, GR antagonists can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone.

[0052] Mifepristone is a GRA which binds to GR and which also binds to a progesterone receptor. As used herein, the term "mifepristone" refers to a family of compositions also referred to as RL i486, or RU38.486, or 17-beta-hydroxy-ll-beta-(4-dimethyl-aminophenyl)-17-alpha-(l- propynyl)-es- tra-4,9-dien-3-one), or 1 l-beta-(4-dimethylaminophenyl)-17-beta-hydroxy-17- alpha-(l-propynyl)-est- ra-4,9-dien-3-one), or analogs thereof, which bind to the glucocorticoid receptor (GR), typically with high affinity, and inhibit the biological effects initiated / mediated by the binding of any cortisol or cortisol analogue to GR. Salts, hydrates and prodrugs of mifepristone are all included in the term “mifepristone” as used herein. Thus, used herein, “mifepristone” refers to the molecule that has the following structure:and to salts, hydrates and prodrugs thereof, and pharmaceutical compositions thereof.

[0053] The duration of treatment with mifepristone can vary according to the severity of the condition in a subject and the subject's response to mifepristone. In some embodiments, administration of mifepristone is continuous. In some embodiments, administration of mifepristone is not continuous and can be stopped for one or more periods of time, followed by one or more periods of time where administration resumes. In some embodiments, mifepristone can be administered for a period of about 1 w'eek to 104 weeks (2 years), more typically about 6weeks to 80 weeks, most typically about 9 to 60 weeks. Suitable periods of administration also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable periods of administration also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88 90, 95, 96, 100, and 104 weeks. Generally administration of mifepristone should be continued until clinically significant reduction or amelioration is observed. Treatment with mifepristone in accordance with the invention may last for as long as two years or even longer.

[0054] As used herein, the terms “administer,” “administering,” “administered” or “administration” refer to providing a compound or a composition (e.g, one described herein), to a subject or patient. For example, a compound or composition may be administered orally to a patient. Administration may be by oral administration (i.e., the subject receives the compound or composition via the mouth, as a pill, capsule, liquid, or in other form suitable for administration via the mouth. Oral administration may be buccal (where the compound or composition is held in the mouth, e.g., under the tongue, and absorbed there). Administration may be by injection, i.e., delivery of the compound or composition via a needle, microneedle, pressure injector, or other means of puncturing the skin or forcefully passing the compound or composition through the skin of the subject. Injection may be intravenous (i.e., into a vein); intraarterial (i.e., into an artery); intraperitoneal (i.e., into the peritoneum); intramusucular (i.e., into a muscle), or by other route of injection. Routes of administration may also include rectal, vaginal, transdermal, via the lungs (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition), or by other route.

[0055] As used herein, the term “effective amount” or “therapeutic amount” refers to an amount of a pharmacological agent, effective to treat, eliminate, or mitigate at least one symptom of the disease being treated. In some cases, “therapeutically effective amount” or “effective amount” can refer to an amount of a functional agent or of a pharmaceutical composition useful for exhibiting a detectable therapeutic or biochemical effect. The effect can be detected by any assay method known in the art.

[0056] .As used herein, the term “combination therapy” refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The at least two agents may be administered according to the same schedule. The at least two agents may be administered simultaneously, or sequentially in any order during the entire or portions of the treatment period. The at least two agents may be administered following the same or different dosing regimens. In some cases, one agent is administered following a scheduled regimen while the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, the one pharmaceutical agent, e.g., mifepristone, is administered daily, and the other pharmaceutical agent, e.g., a CYP3A4 inducer, is administered by a different schedule, e.g., every two, three, or four days.

[0057] As used herein, the term “simultaneously or sequentially administering” refers to administration of two compounds, such as mifepristone and a CYP3A4 inducer, such that the two compounds are in the body at the same time in therapeutically effective amounts.

[0058] As used herein, “concomitant” means at the same, or nearly the same, time, and “concomitantly” refers to actions performed at the same, or nearly the same, time. As used herein, the terms “concurrent” and “concomitant” are equivalent and may be used interchangeably. The adverbs “concurrently” and “concomitantly” are equivalent and may be used interchangeably.

[0059] As used herein, the term “concomitant administration” of two or more drugs means administering two or more drugs at the same, or nearly the same, time. Nearly the same time means that only a short amount of time separates two events, such as administration of a first drug and the administration of a second drug. Concomitant administration of two or more drugs provides therapeutically effective amounts of the two or more drugs in the system of the subject at the same time. Concomitant administration includes administration of a GRA to a patient who has previously been administered a drug, such as a CYP3A4 inducer, and therapeutically effective levels of the CYP3A4 inducer remain in the patient when the patient is administered mifepristone, and includes administration of a CYP3A4 inducer to a patient who has previously- been administered a drug, such as mifepristone, and therapeutically effective levels of mifepristone remain in the patient when the patient is administered the CYP3A4 inducer.

[0060] As used herein, “concomitantly administering drugs” means that two or more drugs are administered to a subject at the same, or nearly the same, time. Drugs that are concomitantlyadministered will each be present in therapeutically effective amounts in the system of the subject at the same time. Nearly the same time means that only a short amount of time separates two events, such as administration of a first drug and the administration of a second drug.

[0061] Events or actions that are “simultaneous” or that occur or are performed “simultaneously” are events that occur or are performed at the same time or nearly the same time.

[0062] As used herein, “at the same time” means that two events occur or are performed within about five minutes of each other.

[0063] As used herein, “nearly the same time” means that two events occur or are performed within about a short time of each other.

[0064] As used herein, a “short time”, a “short amount of time”, a “short period of time”, and the like mean a time that is less than about two hours, or less than about one hour, or less than about 45 minutes, or less than about 30 minutes, or less than about 20 minutes, or less than about 10 minutes, or less than about 7 minutes.

[0065] As used herein, the term "compound" is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety' ("compound") may exist in a free species form, in which it is not associated with other molecules. A compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity. A solvate, in which the molecular moiety of defined chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The recitation of a "compound" refers to the molecular moiety itself (of the recited structure), regardless of whether it exists in a free form or an associated form.

[0066] ,As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients such as the said compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly , from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly orindirectly, in combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are meant to encompass any composition made by admixing compounds of the present invention and their pharmaceutically acceptable carriers.

[0067] “Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptable carrier” refer to a substance that aids the administration of an active agent to --- and absorption by - a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidant agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically-acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavors and colors, and the like. One of ordinary' skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary' active compounds can also be incorporated into the compositions. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0068] As used herein, the term “clinical effect” means changes in symptoms or signs characteristic of, or indicative of, a clinical condition or disorder. For example, where a subject is treated for Cushing’s syndrome, including Cushing’s Disease, a clinical effect may be a change in any one or more of blood pressure, blood glucose, other pre-diabetic symptom, weight, mid- section perimeter, facial characteristics (e.g., change in “moon-face” appearance), immune function, skin thickness, acne, depression or other mood symptom, hirsutism, and other symptoms.

[0069] As used herein, “monitoring for clinical response”, e.g., monitoring a patient for clinical response to a GILA such as mifepristone, may include monitoring the patient (e.g., to identify'- or determine if there are changes in) for glucose control, anti-diabetic medication requirement,insulin level, psychiatric symptoms, Cushingoid appearance, acne, hirsutism, and monitoring the body weight of the patient (e.g., to identify or determine if there are changes in any one or more of these symptoms and characteristics). Monitoring for clinical response may also include monitoring a patient for adverse events, for side-effects of any drug (including a GRA, a CYP3A4 inducer, and other drugs). Thus, monitoring for clinical response may include monitoring for clinical effect of a drug such as a GRM, including clinical efficacy of the GRM; for clinical effect of a CYP3A inducer; for possible adverse reaction to a CYP3A inducer; for possible adverse reaction to the use of a CYP3A4 inducer in combination with mifepristone; for possible side-effects of a CYP3A4 inducer, or their use in combination with mifepristone; or combinations thereof.

[0070] As used herein, the term “AUC” means the area under the plasma concentration-time curve, and serves as a measure of the plasma levels of a drug in a subject to whom the drug has been administered. As used herein, “AUCo-t” is the AUC value measured from time 0 up to time t, where time 0 is the time when a dose of drug was administered.

[0071] As used herein, the term “Cmax” means the maximum observed plasma concentration of a drug in a subject to whom the drug has been administered.

[0072] As used herein, the term “Cmin” means the minimum observed plasma concentration of a drug in a subject to whom the drug has been administered.

[0073] As used herein, the term “Tmax,” means the time, after administration of a drug, at which the plasma levels of the drug reach their maximum level.

[0074] As used herein, the term “CYP enzyme” refers to a cytochrome P450 enzyme. Cytochrome P450 enzymes are important in many metabolic and catabolic reactions in humans and other animals, and play important roles in drug metabolism and action. Drug-drug interactions in which administration of one drug affects the concentration, half-life, activity, or other effect of another drug may include effects on CYP enzymes by induction of CYP enzymes (increasing the amount or activity of one or more CYP enzymes); inhibition (reducing the activity of one or more CYP enzymes); competition (competing for sites or occupying sites, e.g., as a substrate, of one or more CYP enzymes); or by other means. Particular CYP enzymes include, for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes.

[0075] As used herein, a “CYP3A4 inducer” is a compound which increases the activity of the cytochrome CYP3A4, or increases the levels or amounts of CYP3A4 enzymes in the patient(e.g., by increasing the expression of the gene-product of CYP3A4 genes). CYP3A4 inducers may be termed strong or moderate if their administration, along with a test drug known to be metabolized by CYP3A4 enzymes (such as, e.g., rifampin), decreases the AUC (area under the concentration curve) of the test drug. A strong CYP3A4 inducer is a drug that decreases the AUC of sensitive substrates of CYP3A4 by >80 percent. A moderate inducer is a drug that decreases the AUC of sensitive substrates of CYP3A4 by >50 to <80 percent. Inducers of CYP3A4 include, for example, rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, mitotane, carbamazepine, and St. John's wort Strong inducers of CYP3A4 include rifapentine, phenytoin, mitotane, and carbamazepine.I. COMBINATION THERAPIES

[0076] V arious combinations with mifepristone and a CYP3 A4 inducer (or a combination of such agents and compounds) may be employed to treat the patient. By “combination therapy” or “in combination with”, it is not intended to imply that the therapeutic agents must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope described herein. Mifepristone and the CYP3A4 inducer can be administered following the same or different dosing regimen. In some embodiments, mifepristone and the CYP3A4 inducer are administered sequentially in any order during the entire or portions of the treatment period. In some embodiments, mifepristone and the CYP3A4 inducer is administered simultaneously or approximately simultaneously (e.g., within about 1 , 5, 10, 15, 20, or 30 minutes of each other). Non-limiting examples of combination therapies are as follows, with administration of mifepristone and the CYP3A4 inducer for example, mifepristone is “A” and the CYP3 A4 inducer is "B":

[0077] A / B / AB / A / BB / B / AA / A''BA / B / BB / A / AA / B / B / B B / A'B / B

[0078] B / B / B / A B / B / A / B A / A / B / B A'B / A'B A / B / B / A B / B / A / A

[0079] B / A / B / A B / A / A / B zVA / A / B B / A / A / A A / B / A / A A / A / B / A

[0080] Administration of the therapeutic compounds or agents to a patient wall follow general protocols for the administration of such compounds, taking into account the toxicity, if any, of the therapy. Surgical intervention may also be applied in combination with, before, or after administration of therapeutic compounds.

[0081] The present methods can be combined with other means of treatment such as surgery, radiation, targeted therapy, immunotherapy, use of growth factor inhibitors, or anti-angiogenesis factors.

[0082] The foilowing example is provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar resuits.EXAMPLE

[0083] As shown in FIG. 1, administration of the CYP3A4 inducer rifampin reduced the plasma level of mifepristone. FIG. 1 presents the geometric mean plasma concentrations of mifepristone after oral administration of a single 1500 mg dose of mifepristone before and after dosing for 14 days with rifampin 600 mg QD to healthy volunteers. The left-hand graph shows mean plasma mifepristone concentration in a linear plot, while the right-hand graph shows mean plasma mifepristone concentration in a semi-logarithmic plot.

[0084] As disclosed in Table 1, the CYP3A4 inducer rifampin reduced mifepristonereduced mifepristone Tmax, and reduced mifepristone AUCo-t.TABLE 1* Geometric mean [geometric CV%] (N) except Tmax for which the median (N) [Range] is reportedTable 1 : Summary of pharmacokinetic parameters for mifepristone and statistical comparison after oral administration of a single 1500 mg dose of mifepristone before and after dosing for 14 days with rifampin 600 mg QD to healthy volunteers.

[0085] Table 2 provides pharmacokinetic parameters I max, Cmax, Cmin, and AUCO-24.TABLE 2Table 27. .Mifeprfehhie aed Mehfefe interval PK hramelers by Study DayData were from subjects who received a 600 nig dose of mifepristone once a day given with 20 nig prednisone on days -7, 1, 7 and 14.

[0086] As illustrated by the results disclosed herein, concomitant administration of mifepristone and rifampin led to reductions of less than about 50% in the mifepristone Cmax, in the mifepristone Tmilx, and in the mifepristone AUQo-o. Thus, twice the original amount of mifepristone could be safely administered to patients receiving concomitant CYP3A4 inducers such as rifampin.

[0087] All patents, patent publications, publications, and patent applications cited in this specification are hereby incorporated by reference herein in their entireties as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In addition, although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary’ skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WE CLAIM:

1. A method of safely treating a Cushing’s Syndrome patient who is in need of concomitant treatment with mifepristone and with a CYP3A4 inducer, comprising: administering an original dose of mifepristone for at least 7 days; then administering an effective dose of said CYP3A4 inducer; then administering an increased dose of mifepristone, wherein said increased dose of mifepristone is about twice the dose of said original dose of mifepristone, and is less than about 3000 milligrams (mg) mifepristone; wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said CYP3A4 inducer, whereby the patient is safely treated with both mifepristone and a CYP3A4 inducer.

2. The method of claim 1, wherein said increased dose of mifepristone is about three times the dose of said original dose of mifepristone, and is less than about 3000 mg of mifepristone.

3. The method of claim 1 or claim 2, wherein the CYP3 A4 inducer is selected from mitotane, rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort,4. The method of any of claims 1 to 3, wherein the CYP3A4 inducer is rifampin,5. The method of any of claims 1 to 3, wherein the CYP3A4 inducer is mitotane.

6. The method of any of claims 1 to 3, wherein the need for treatment with a CYP3A4 inducer comprises need to treat a disorder selected from an adrenal tumor, hypertension, bacterial infection, tuberculosis, and meningitis, and said effective dose of said CYP3A4 inducer is effective to treat said disorder.

7. The method of any of claims 1 to 6, wherein said original dose of mifepristone is selected from the group consisting of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg.

8. The method of any of claims 1 to 7, wherein said CYP3A4 inducer is rifabutin, and said CYP3A4 inducer dose is selected from the group consisting of about 300 milligrams (mg), about 600 mg, and about 900 mg; or said CYP3A4 inducer is mitotane, and said CYP3A4 inducer dose is selected from the group consisting of about 2 grams (g), about 4 g, and about 6 g;or said CYP3A4 inducer is rifampin, and said CYP3A4 inducer dose is selected from the group consisting of about 300 mg, about 600 mg, and about 900 mg; or said CYP3A4 inducer is rifapentine, and said CYP3A4 inducer dose is selected from the group consisting of about 200 mg, about 400 mg, and about 600 mg; or said CYP3A4 inducer is phenobarbital, and said CYP3A4 inducer dose is selected from the group consisting of about 50 mg, about 200 mg, and about 300 mg; or said CYP3A4 inducer is phenytoin, and said CYP3A4 inducer dose is selected from the group consisting of about 100 mg, about 300 mg, and about 500 mg.

9. The method of any of claims 1, 2, 6, or 7, wherein said CYP3A4 inducer is an antihypertensive medication, and wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said antihypertensive medication that is a CYP3A4 inducer.

10. The method of any of claims 1 to 9, wherein said Cushing’s Syndrome patient is at risk for increasing liver enzyme levels in the blood due to administration of said CYP3A4 inducer, wherein, during said co-administration of mifepristone with said CYP3A4 inducer the liver enzyme levels in the blood of the patient remain lower than the liver enzyme levels expected in a patient receiving said CYP3A4 inducer in the absence of mifepristone pretreatment, whereby the patient is safely treated with both mifepristone and a CYT3A4 inducer.

11. The method of any of claims 1 , 2, 6, 7, 9, or 10, wherein said method is further effective to control hypertension in a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer, whereby the patient is safely treated with both mifepristone and a CYP3 A4 inducer effective to aid in the control of hypertension in said patient.

12. The method of any of claims 1, 2, 6, 7, 9, 10, or 11, wherein said method is further effective to improve the efficacy of anti-hypertensive medications in a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer, said patient receiving mitotane, wherein said hypertension is treatable by administration of an antihypertensive medication, wherein said antihypertensive medication is metabolized by CYP3A4, wherein said coadministration of said increased dose of mifepristone with said antihypertensive medication that is metabolized by CYP3A4 inducer is effective to improve the efficacy of said hypertensive medication in the patient as compared to the effectiveness of said hypertensive medication in the absence of pre- treatment with mifepristone.

13. The method of claim 12, wherein said antihypertensive medication that is metabolized by CYP3A4 is selected from amlodipine, bisoprolol, carvedilol, diltiazem, eplerenone, felodipine, indapamide, isradipme, nifedipine, nimodipine, nisoldipine, and nitrendipine.

14. The use of mifepristone and a CYP3A4 inducer for safely treating a Cushing’s Syndrome patient who is in need of concomitant treatment with mifepristone and with a CYP3A4 inducer, the use comprising:Use of an original dose of mifepristone for at least 7 days; thenUse of an effective dose of said CYP3A4 inducer; thenU se of an increased dose of mifepristone that is about twice the amount of said original dose of mifepristone, and is less than about 3000 milligrams (mg) mifepristone.

15. The use of claim 14, wherein said increased dose of mifepristone is about three times the dose of said original dose of mifepristone, and is less than about 3000 mg of mifepristone.

16. The use of claim 14 or claim 15, wherein the CYP3A4 inducer is selected from mitotane, rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort.

17. The use of any of claims 14 to 16, wherein the CYP3A4 inducer is rifampin.

18. The use of any of claims 14 to 16, wherein the CYP3A4 inducer is mitotane.

19. The use of any of claims 14 to 16, wherein the need for treatment with a CYT3A4 inducer comprises need to treat a disorder selected from an adrenal tumor, hypertension, bacterial infection, tuberculosis, and meningitis, and said effective dose of said CYP3A4 inducer is effective to treat said disorder.

20. The use of any of claims 14 to 19, wherein said original dose of mifepristone is selected from the group consisting of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg.

21. The use of any of claims 14 to 19, wherein said CYP3A4 inducer is rifabutin, and said CYP3A4 inducer dose is selected from the group consisting of about 300 milligrams (mg), about 600 mg, and about 900 mg; or said CYP3A4 inducer is mitotane, and said CYP3A4 inducer dose is selected from the group consisting of about 2 grams (g), about 4 g, and about 6 g; or said CYP3A4 inducer is rifampin, and said CYP3A4 inducer dose is selected from the groupconsisting of about 300 mg, about 600 mg, and about 900 mg; or said CYP3A4 inducer is rifapentine, and said CYP3A4 inducer dose is selected from the group consisting of about 200 nig, about 400 mg, and about 600 mg; or said CYP3A4 inducer is phenobarbital, and said CYP3A4 inducer dose is selected from the group consisting of about 50 mg, about 200 nig, and about 300 mg; or said CYP3A4 inducer is phenytoin, and said CYP3A4 inducer dose is selected from the group consisting of about 100 mg, about 300 mg, and about 500 mg.

22. The use of any of claims 14 to 20, wherein said CYP3A4 inducer is an antihypertensive medication, and wherein said increased dose of mifepristone is effective to safely treat Cushing’s Syndrome in said patient while the patient is receiving concomitant administration of said antihypertensive medication that is a CYP3A4 inducer.

23. The use of any of claims 14 to 22, wherein said Cushing’s Syndrome patient is at risk for increasing liver enzyme levels in the blood due to administration of said CYP3A4 inducer, wherein, during said co-administration of mifepristone with said CYP3A4 inducer the liver enzyme levels in the blood of the patient remain lower than the liver enzyme levels expected in a patient receiving said CYP3A4 inducer in the absence of mifepristone pre-treatment, whereby the patient is safely treated with both mifepristone and a CAT3A4 inducer.

24. The use of any of claims 14 to 20, 22, or 23, wherein said use is for controlling hypertension in a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer.

25. The use of any of claims 14 to 20, 22, 23, or 24, wherein said use is for improving the efficacy of anti-hypertensive medications in a patient suffering from Cushing’s syndrome and suffering from adrenocortical cancer, said patient receiving mitotane, wherein said hypertension is treatable by administration of an antihypertensive medication, wherein said antihypertensive medication is metabolized by CYP3A4.

26. The use of claim 25, wherein said antihypertensive medication that is metabolized by CYP3A4 is selected from amlodipine, bisoprolol, carvedilol, diltiazem, eplerenone, felodipme, indapamide, isradipine, nifedipine, nimodipine, nisoldipine, and nitrendipine.

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