Methods for treating Cushing's syndrome and liver damage, and for reducing hepatotoxicity of other drugs administered to a patient - Patents.com

Abstract

Disclosed are methods and uses for treating subjects suffering from disorders selected from liver disorders, Cushing's syndrome or Cushing's disease, cancer, infectious diseases, inflammatory conditions, cardiovascular diseases, endocrine diseases, or kidney diseases, and combinations thereof, or other disorders that may be administered drugs that may cause liver toxicity, without adverse effects on the liver. Such liver disorders include fatty liver disease, and are effective in reducing high levels of liver enzymes with a favorable safety profile. The methods and uses include administering to a subject an effective amount of a selective nonsteroidal glucocorticoid receptor modulator, such as relacorilant, including methods and uses in combination with other drugs without adverse effects on liver enzyme levels or liver function. In some embodiments, the other drugs may be drugs that may cause liver toxicity, such as drugs that inhibit CYP3A enzymes, for example, itraconazole or ketoconazole.

Description

[Background technology]

[0001] Relacorilant (also known as CORT125134) binds to the glucocorticoid receptor type 2 (GR) and is a highly selective GR modulator (SGRM). It is in clinical development for the treatment of endogenous hypercortisolism of all etiologies (monotherapy) (including Cushing's disease (CD), Cushing's syndrome (CS)), adrenocortical carcinoma, and other solid tumors (including anticancer agents). Relacorilant lacks affinity for the progesterone receptor (unlike the FDA-approved GR antagonist mifepristone). Studies of Cushing's syndrome indicate that relacorilant administration can provide clinically meaningful improvement in hypertension and hyperglycemia without antiprogesterone effects or drug-induced hypokalemia. Improvements in other observed cortisol excess-related comorbidities, including hypercoagulability, cognitive function, mood, and quality of life, have also been observed in these patients.

[0002] Elimination of administered relacorilant is primarily hepatic (via CYP3A and carbonyl reductase). Although it is a potent CYP3A4 inhibitor, its administration does not result in clinically significant inhibition of CYP2C8 or CYP2C9. Thus, it appears to interact with the liver and other enzymes.

[0003] However, many drugs that affect the glucocorticoid receptor (GR) or the levels or effects of cortisol have significant effects on the liver. Many patients are administered drugs that can cause hepatotoxicity. For example, some drugs, such as ketoconazole and itraconazole, can result in hepatotoxicity. However, there are patients who can be administered drugs that can cause hepatotoxicity and drugs that affect GR. For example, excessive cortisol levels, as is often seen in Cushing's syndrome, can lead to or are often accompanied by high levels of liver fat, high levels of liver enzymes (e.g., alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), nonalcoholic steatohepatitis (NASH), and other liver disorders. Such excessive cortisol levels can be treated with drugs that affect GR.

[0004] Liver disorders can be classified into various disease groups, such as alcohol-induced fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), drug- or alcohol-related liver disease, viral diseases, immune-mediated liver disease, metabolic liver disease, and complications associated with liver failure and / or liver transplantation. Non-alcoholic fatty liver disease is a common liver disorder with histological features similar to alcohol-induced fatty liver disease in individuals with little or no alcohol intake. Fatty liver disease results from abnormal accumulation of lipids (fat) in hepatocytes. Effective treatments for AFLD and NAFLD remain insufficient. To date, no therapeutic drug has been established for such patients. Novel treatment options for managing fatty liver disease are needed. Novel treatment options are needed for patients who require treatment with both drugs that can cause hepatotoxicity and drugs that affect GR. Summary of the Invention [Means for solving the problem]

[0005] The present method provides an improved method of administering selective glucocorticoid receptor modulators (SGRMs) and drugs that may cause liver toxicity to patients in need thereof. Disclosed herein is a novel method for treating Cushing's syndrome and Cushing's disease with a favorable liver safety profile. Also disclosed herein is a novel method for treating liver disorders, including fatty liver disease, reducing high liver enzyme levels, and for other treatments, all with favorable liver safety profiles. Applicants disclose herein a favorable liver safety profile of the SGRM Relacorilant after administration to healthy adults and adults with liver disorders, as well as patients with Cushing's syndrome. The present method includes administering an effective amount of Relacorilant to a subject without adverse effects on liver enzyme levels or liver function. In an embodiment, the method includes administering an effective amount of Relacorilant to a subject in combination with another drug without adverse effects on liver enzyme levels or liver function. In some embodiments, the method includes a method of reducing or preventing hepatotoxicity in a patient receiving a drug that can cause hepatotoxicity, the method includes administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) in addition to the drug that can cause hepatotoxicity. In some embodiments, the patient is administered a drug that can cause hepatotoxicity and then an SGRM. In some embodiments, the patient is administered an SGRM and then an drug that can cause hepatotoxicity. In some embodiments, the other drug may be a drug that can inhibit CYP3A enzymes (including CYP3A4 enzymes), such as itraconazole or ketoconazole. In some embodiments, the method includes reducing hepatic steatosis in a patient suffering from liver damage, Cushing's syndrome, Cushing's disease, or a combination thereof, by administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) effective to reduce hepatic steatosis in the patient.In one embodiment, the method includes, when a subject is being or will be administered a drug with known hepatotoxicity (e.g., itraconazole, ketoconazole, or other CYP3A inhibitor), co-administering relacorilant in an amount effective to reduce, prevent, or eliminate the hepatotoxicity of the drug with known hepatotoxicity.

[0006] Relacorilant is a heteroaryl-ketone fused azadecalin compound disclosed and described in Example 18 of U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference in their entirety. The chemical name of Relacorilant is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, and has the following structure: [ka]

[0007] The applicant has discovered and disclosed herein that lelacorilant has a favorable hepatic safety profile, including a trend toward improved liver function tests (LFTs), in healthy volunteers and in patients with normal and impaired liver function. The applicant has discovered and disclosed herein that lelacorilant can be safely administered to patients with moderate liver impairment as well as to patients with normal liver function. Thus, SGRMs such as lelacorilant can be administered to patients with impaired liver function in the same manner, dosage, and frequency of administration as they are administered to patients with normal liver function. Findings in patients with impaired liver function support the use of lelacorilant in treating patients with Cushing's disease and patients with Cushing's disease who have moderate liver impairment without the need for adjustment of the amount of lelacorilant (compared to the dose used in patients without moderate liver impairment). Findings in patients with impaired liver function also support the use of lelacorilant in treating patients with impaired liver function who have moderate liver impairment without the need for adjustment of the amount of lelacorilant (compared to the dose used in patients without liver impairment). Relacorilant can be administered in the treatment of liver disorders, including fatty liver disorders.Fatty liver disorders include, for example, alcohol-related liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and other liver disorders.SGRM such as Relacorilant can be administered to patients suffering from cancer, patients suffering from fungal infection, or patients suffering from other disorders that may be co-administered with drugs that may cause liver toxicity, without the need to adjust the dose of Relacorilant (compared to the dose used in the absence of drugs that may cause liver toxicity).

[0008] Relacorilant may be administered orally or by any other suitable means. In the studies disclosed herein, Relacorilant was administered orally at a dose of 100 milligrams (mg) to 400 mg per day. Relacorilant may be administered once a day, or two or three times a day, or other times.

[0009] In embodiments of the methods disclosed herein, an effective amount of Relacorilant may include a daily dose of 1-100 mg / kg per day. In some embodiments, the daily dose of Relacorilant is 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg per day. Relacorilant may be administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, 40 weeks, 45 weeks, 50 weeks, 55 weeks, 60 weeks, 65 weeks, 70 weeks, 75 weeks, or 80 weeks.

[0010] The present invention provides an improved method of treating patients who are administered SGRMs and drugs that may cause hepatotoxicity to the patient.The present invention provides an improved method of treating liver disorders, including Cushing's syndrome, Cushing's disease, and fatty liver disease, excessive liver enzyme levels, and other liver disorders.The present invention provides an improved method of reducing fatty liver in patients suffering from liver disorders, Cushing's syndrome, Cushing's disease, or a combination thereof.The present invention provides an improved method of reducing, preventing, or eliminating the hepatotoxicity of known hepatotoxic drugs by administering an SGRM, such as relacorilant, with the known hepatotoxic drug. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the results of a liver damage test.

[0012] [Diagram 2] FIG. 1 shows the results of a drug interaction test (Relacorilant-Itraconazole).

[0013] [Diagram 3] FIG. 1 shows the results of a Phase 2 Cushing's Syndrome study.

[0014] [Figure 4] FIG. 1 shows the study design of the ongoing clinical trial. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Disclosed are methods and uses for treating subjects suffering from disorders selected from liver disorders, Cushing's syndrome or Cushing's disease, cancer, infectious diseases, inflammatory conditions, cardiovascular diseases, endocrine diseases, or kidney diseases, and combinations thereof, or other disorders that may be administered drugs that may cause liver toxicity, without adverse effects on the liver. Such liver disorders include fatty liver disease, and are effective in reducing high levels of liver enzymes with a favorable safety profile. The methods and uses include administering to a subject an effective amount of a selective nonsteroidal glucocorticoid receptor modulator, such as relacorilant, including methods and uses in combination with other drugs without adverse effects on liver enzyme levels or liver function. In some embodiments, the other drug may be a drug that inhibits CYP3A enzymes, such as itraconazole or ketoconazole, that may cause liver toxicity.

[0016] Therefore, the applicant herein discloses an improved method for administering a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to a patient who may be administered another drug that may cause hepatotoxicity, without adverse effects on the patient's liver. The SGRM may be, for example, a heteroaryl-ketone fused azadecalin compound, and in some embodiments, may be lelacorilant. The applicant herein discloses that an SGRM such as lelacorilant can be administered to either a patient with a normal liver or a patient with moderate liver damage at the same dosage. The applicant herein discloses that an SGRM such as lelacorilant can be administered to either a patient who is not administered a drug that may cause hepatotoxicity, or a patient who is administered or will be administered a drug that may cause hepatotoxicity at the same dosage. An SGRM such as lelacorilant can be administered to a patient with impaired liver function in the same manner, dosage, and frequency of administration as it is administered to a patient with normal liver function.

[0017] The methods disclosed herein include a method of treating a patient who is or will soon be administered a drug that can cause hepatotoxicity without adverse effects on the patient's liver, comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat a patient who is or will soon be administered a drug that can cause hepatotoxicity without adverse effects on the patient's liver. In an embodiment, the method includes a method in which the patient is administered a drug that can cause hepatotoxicity and then is administered an SGRM. In an embodiment, the method includes a method in which the patient is administered an SGRM and then is administered a drug that can cause hepatotoxicity. In an embodiment, the SGRM is a relacorilant. In an embodiment, the patient is suffering from Cushing's syndrome, Cushing's disease, liver disease, cancer, or other disorder in which the patient may be administered a drug that can cause hepatotoxicity.

[0018] Applicants herein disclose the use of an SGRM, such as relacorilant, to reduce or prevent hepatotoxicity in patients who have been administered or will soon be administered a drug that can cause hepatotoxicity, which includes the use of an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) in combination with (before or after) a drug that can cause hepatotoxicity. In one embodiment, the patient has been administered a drug that can cause hepatotoxicity, and then the SGRM is administered. In one embodiment, the patient has been administered a SGRM, and then the drug that can cause hepatotoxicity is administered. In one embodiment, the SGRM is relacorilant.

[0019] The methods and uses disclosed herein can be used to treat patients suffering from Cushing's syndrome, Cushing's disease, or liver damage by administering an effective amount of a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM). In some embodiments, the GRM administration may be combined with other medicaments or medical treatments effective for treating liver damage. In a preferred embodiment, the SGRM is a non-steroidal SGRM, such as a compound comprising a fused azadecalin structure. In some embodiments, the non-steroidal SGRM is a compound comprising a heteroaryl-ketone fused azadecalin structure.

[0020] Applicant discloses a method of treating a patient suffering from Cushing's syndrome, Cushing's disease, liver damage, or cancer, or a combination thereof, without adverse effects on the patient's liver, comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the liver damage or Cushing's syndrome without adverse effects on the patient's liver. Applicant discloses herein a method of treating a patient suffering from Cushing's syndrome, Cushing's disease, liver damage, cancer, fungal infection, bacterial infection, viral infection, inflammatory disease or condition, cardiovascular disease, endocrine condition, renal disease, or a combination thereof, without adverse effects on the patient's liver, comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the disorder without adverse effects on the patient's liver.

[0021] Applicants disclose herein a method for reducing hepatic steatosis in a patient suffering from liver damage, Cushing's syndrome, Cushing's disease, or a combination thereof, comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce hepatic steatosis in the patient.

[0022] Applicant herein discloses a method for reducing or preventing liver toxicity in a patient receiving a drug that can cause liver toxicity, comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) in addition to the drug that can cause liver toxicity. Many different drugs have been implicated in liver toxicity (see, e.g., Bjornsson et al, Int. J. Mol. Sci. 2016, 17, 224-230; and Chen et al., Drug Discov Today. 2016, 21(4): 648-653). A ranked list of drugs (ranked in order of severity of liver injury) can be downloaded from the U.S. Food and Drug Administration website "fda.gov" under the title "Drug-Induced Liver Injury Rank (DILIrank) Dataset." The DILIrank dataset consists of 1,036 FDA-approved drugs divided into three classes according to their potential to cause drug-induced liver injury (DILI) and a fourth group of drugs for which data on liver toxicity are equivocal. Of the 1,036 drugs discussed, 192 were considered to be of greatest concern, 278 were considered to be of less concern compared to the drugs of greatest concern, and for 254 drugs the analysis was equivocal, leaving 312 of the 1,036 found to be of no concern with regard to drug-induced liver injury.

[0023] In one embodiment, the drug that may cause hepatotoxicity is a drug listed in the DILIrank dataset. In one embodiment, the drug that may cause hepatotoxicity is a drug identified in the DILIrank dataset as "most DILI concern" or "least DILI concern". In one embodiment, the drug that may cause hepatotoxicity is a drug identified in the DILIrank dataset as "most DILI concern". The 192 drugs identified in the DILIrank dataset as most DILI concern are mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetacarbazine, cefotaxime ... rol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, Zide, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan , oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacran, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisxocin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benziodarone, atomoxetine, chlormezanone,Erlotinib, Cincophen, Tipranavir, Clometacin, Sorafenib, Darunavir, Cyclofenil, Didanosine, Interferon α-2b, Interferon α-2a, Recombinant, Droxicam, Ethambutol, Infliximab, Exifon, Fialuridine, Fipexide, Fosphenytoin, Gemcitabine, Levofloxacin, Mebanazine, Moxisylyte, Nialamide, Nilutamide, Niperotidine, Nomifensine, Nortol Liptiline, pirprofen, riluzole, ritonavir, suloctidil, tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, Oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythropoietin, Mycobacterium tuberculosis, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alpha-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

[0024] In some embodiments, the drug that may cause hepatotoxicity is a CYP3A inhibitor. In some embodiments, the drug that may cause hepatotoxicity is ketoconazole or itraconazole. In some embodiments, the drug that may cause hepatotoxicity is selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

[0025] In some embodiments, the patient is suffering from Cushing's syndrome, hi some embodiments, the patient is suffering from Cushing's syndrome and liver damage.

[0026] In some embodiments, the liver disorder is fatty liver disease. In some embodiments, the fatty liver disease is selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD). In some embodiments, the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH) or alcoholic cirrhosis. In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

[0027] The nonsteroidal selective glucocorticoid receptor modulator may be a compound that comprises a heteroaryl-ketone fused azadecalin structure.In some embodiments, the nonsteroidal selective glucocorticoid receptor modulator is a relacorilant, that is, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: [ka]

[0028] The methods disclosed herein may further comprise administering to the patient an additional pharmaceutical composition without additional adverse effects on the patient's liver. In some embodiments, the additional pharmaceutical composition comprises itraconazole or ketoconazole. In some embodiments, the additional pharmaceutical composition comprises a CYP3A inhibitor. In some embodiments, the additional pharmaceutical composition comprises a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole. In certain embodiments, the additional pharmaceutical composition is selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, Nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacran, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin,Paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benziodarone, atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon alpha-2b, interferon alpha-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fialuridine, fipexide, Fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidil, tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaproclate, oropyridine. Lurisat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetamivir The present invention includes drugs selected from the group consisting of acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alpha-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

[0029] Current testing of Relacorilant in patients with endogenous hypercortisolism (e.g., Cushing's syndrome in patients with Cushing's disease) includes liver function test (LFT) evaluation. In some embodiments, LFT evaluation includes measuring alanine aminotransferase (ALT) levels, measuring aspartate aminotransferase (AST) levels, or both. LFT evaluation may further include magnetic resonance imaging (MRI) of the liver, computer-assisted tomography (CAT) imaging of the liver, liver biopsy, and other tests. Other clinical parameters of the patient may be determined, including, for example, blood pressure, blood glucose level, Hb1Ac level, blood potassium level, weight, glucose tolerance measurement, insulin level, blood coagulation measurement, patient cognitive function, patient mood, quality of life, and other measurements.

[0030] b.Definition Cushing's syndrome is a condition caused by the overproduction of the glucocorticoid cortisol by the adrenal cortex. The condition is often due to the presence of a tumor or hyperplasia that exhibits unregulated secretion of adrenocorticotropic hormone (ACTH). Unregulated secretion of ACTH in turn causes the adrenal glands to secrete excess cortisol. Cortisol is generally involved in a negative feedback loop in which high levels of cortisol suppress the secretion of both ACTH and cortisol. However, in Cushing's syndrome, this negative regulation is ineffective or absent, resulting in chronic hypercortisolemia.

[0031] Hepatic enzymes are important in the utilization of food, maintaining homeostasis in organisms (including human patients), and may play an important role in the metabolism of pharmaceutical compounds administered to patients. Such hepatic enzymes, such as CYP2C8, CYP2C9, CYP3A4, and other CYP enzymes, which may also be present in other tissues, include alanine aminotransferase (ALT), aspartate aminotransferase (AST). Such enzymes are described, for example, in U.S. Patent Nos. 10,195,214 and 11,285,145, the entire contents of which are incorporated herein by reference.

[0032] As used herein, the terms "hepatotoxicity" and "liver toxicity" refer to liver damage and / or toxic liver disease caused by administration of drugs (including pharmacological and herbal remedies), exposure to solvents, ingestion of toxic foods (e.g., poisonous mushrooms), or other physical insults that can damage the liver.

[0033] As used herein, the terms "drugs that can cause hepatotoxicity," "agents that can cause hepatotoxicity," "hepatotoxic drugs," and "hepatotoxic agents" refer to drugs and agents that can cause liver damage and / or toxic liver disease. Such drugs and agents can be, for example, but are not limited to, medications, herbal remedies, solvents, toxic foods (e.g., toxic mushrooms), and other agents that can damage the liver.

[0034] Drugs that may cause hepatotoxicity include, but are not limited to, mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudizol. sulindac, tamoxifen, tizanidine, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole , sulfathiazole, terbinafine, ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrin, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, benoxypropazine, Dazac, Benzarone, Benziodarone, Atomoxetine, Chlormezanone, Erlotinib, Cincophen, Tipranavir, Clometacin, Sorafenib, Darunavir, Cyclofenil, Didanosine, Interferon α-2b, Interferon α-2a, Recombinant, Droxicam, Ethambutol, Infliximab, Exifon, Fialuridine, Fipexide, Fosphenytoin, Gemcitabine, Levofloxacin, Mebanazine, Moxisylyte, Nialamide, Nilutamide, Niperotidine, Nomifensine, Nortriptyline, Pirprofen,Riluzole, ritonavir, suloctidil, tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelizine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz , interferon beta-1b, interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alpha-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

[0035] As used herein, the term "liver disorder" and "liver disease" refers to liver disorder or disease.Liver disorder includes, but is not limited to, fatty liver disease, alcohol-related liver disease, non-alcoholic fatty liver disease, hepatitis, and other liver disorders.Liver disorder is described, for example, in U.S. Patent No. 10,238,659, the entirety of which is incorporated herein by reference.

[0036] "Fatty liver disease" refers to a disease or pathological condition caused, at least in part, by abnormal hepatic lipid deposits. Fatty liver disease includes, for example, alcoholic fatty liver disease, nonalcoholic fatty liver disease, and acute fatty liver of pregnancy. Fatty liver disease can be, for example, macrovesicular steatosis or microvesicular steatosis.

[0037] "Alcohol-related liver disease" or "ARLD" refers to a disease of the liver caused or resulting in whole or in part from excessive alcohol consumption. There are four major types of ARLD: alcoholic fatty liver (AFL, a subtype of fatty liver disease), alcoholic steatohepatitis (ASH), alcoholic cirrhosis, and alcoholic hepatocellular carcinoma. As used herein, "excessive alcohol consumption" generally refers to the intake of more than about 15-30 g / day of ethanol.

[0038] The physiological effect of alcohol intake on liver function or liver disease depends on various genetic and non-genetic factors that modify both individual susceptibility and the clinical course of ARLD.Thus, in certain patients, ARLD may develop at much lower rates of alcohol intake, including at least about 12g / day, 15g / day, 20g / day, 25g / day or more.Furthermore, it is understood that in some patients, the estimate of daily alcohol intake is an average value that includes periods of heavy alcohol intake and periods of little or no alcohol intake.Such average values ​​can include the average of alcohol intake over at least about 1 week, 2 weeks, 1 month, 3 months, 6 months, 9 months, 1 year, 2 years, 3 years, or 4 years or more. In some cases, the determination of whether liver dysfunction is ARLD is based on reference to a variety of factors, including, but not limited to, the amount and type of alcoholic beverage intake (e.g., beer or distilled spirits); the duration of alcohol abuse; the pattern of drinking behavior (e.g., binge drinking, binge drinking without concomitant food intake, etc.); gender; ethnicity; coexisting disease conditions such as metabolic syndrome or diabetes, iron overload, or hepatitis viral infection, genetic markers; family history; liver enzyme levels; inflammatory cytokine levels; gene or protein expression analysis; or histopathological examination of liver tissue or liver cells.

[0039] "Liver damage not related to excessive alcohol consumption" is liver damage that is differentiated from ARLD. Thus, such damage refers to a wide range of liver diseases that are not caused by alcohol consumption. For example, hepatitis can be caused by viral infection. Liver damage caused by excessive alcohol consumption and other factors is considered ARLD, not liver damage not related to excessive alcohol consumption. In contrast, liver damage that is simply aggravated by excessive alcohol consumption is considered to be liver damage unrelated to excessive alcohol consumption.

[0040] "Nonalcoholic fatty liver disease" or "NAFLD" refers to fatty liver disease characterized by the presence of fat (lipids) in the liver, without substantial inflammation or liver toxicity. NAFLD can progress to nonalcoholic steatohepatitis, which can then progress to irreversible advanced liver scarring or cirrhosis.

[0041] "Nonalcoholic steatohepatitis" or "NASH" refers to fatty liver disease that is similar to alcoholic liver disease but occurs in people who drink little or no alcohol. The main feature in NASH is fat in the liver, in addition to inflammation and damage. NASH can lead to cirrhosis, where the liver becomes permanently damaged and scarred and can no longer function properly. The differential diagnosis of NASH vs. NAFLD can be determined by liver biopsy.

[0042] As used herein, the term "patient" refers to a human who is receiving, will be receiving, or has received medical treatment for a disease or condition.

[0043] As used herein, the terms "administer", "administering", "administered" or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. Administration may be by oral administration (i.e., the subject is administered the compound or composition orally, as a pill, capsule, liquid, or in other form suitable for oral administration). Oral administration may be buccal (where the compound or composition is held in the mouth, e.g., under the tongue, where it is absorbed). Administration may be by injection, i.e., delivery of the compound or composition by needle, microneedle, pressurized syringe, or other means that pierces the skin or forces the compound or composition through the subject's skin. Injection may be intravenous (i.e., intravenously); intraarterial (i.e., intraarterial); intraperitoneal (i.e., intraperitoneally); intramuscular (i.e., intramuscular); or by other injection routes. Routes of administration may also include rectal, vaginal, transdermal, pulmonary (eg, by inhalation), subcutaneous (eg, by absorption through the skin from an implant containing the compound or composition), or by other routes.

[0044] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacological agent effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to an amount of a functional agent or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. An effective amount may be an amount effective to cause an anti-tumor response. For purposes of this disclosure, an effective amount of an SGRM or an effective amount of a chemotherapeutic agent is an amount that treats liver damage or produces other desired beneficial clinical outcomes associated with the treatment of liver damage.

[0045] As used herein, the term "combination therapy" refers to the administration of two or more pharmaceutical agents to a subject to treat a disease. The two agents can be administered simultaneously or sequentially in any order during all or part of the treatment period. The two or more agents can be administered according to the same or different dosing regimens. In some cases, one agent is administered after a scheduled regimen and the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, one agent, e.g., an SGRM, is administered daily and the other agent, e.g., a chemotherapeutic agent, is administered every 2, 3, or 4 days.

[0046] As used herein, the term "compound" is used to indicate a molecular moiety of a unique, identifiable chemical structure. A molecular moiety ("compound") may exist in the form of a free species where it is not associated with other molecules. A compound may also exist as part of a larger aggregate where it is associated with other molecules, but nevertheless retains its chemical identity. A solvate where a molecular moiety ("compound") of a defined chemical structure is associated with molecules of a solvent is an example of such an associated form. A hydrate is a solvate where the associated solvent is water. The recitation of "compound" refers to the molecular moiety itself (of the recited structure), regardless of whether it exists in a free or associated form.

[0047] As used herein, the term "composition" is intended to encompass products that contain specified components, such as the compounds disclosed herein, as well as specific amounts of their tautomers, derivatives, analogs, stereoisomers, polymorphs, deuterated species, pharma- ceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, pharma- ceutically acceptable solvates, and pharma- ceutically acceptable compositions, as well as any product that results directly or indirectly from the combination of specified components in specific amounts. The pharmaceutical compositions discussed herein are meant to encompass any composition made by mixing the aforementioned compounds and their pharma- ceutical acceptable carriers.

[0048] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. These terms refer to any substance that aids in the administration of an active agent to, and absorption by, a subject, and may be included in a pharmaceutical composition without causing significant adverse toxic effects to the patient. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical composition is contemplated. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings, and coloring agents, and the like. Those skilled in the art will recognize that other pharmaceutical excipients may be useful as well.

[0049] As used herein, the phrase "non-steroidal backbone" in the context of SGRMs refers to SGRMs that do not share structural homology with, or are not modifications of, cortisol, which has a steroidal backbone containing 17 carbon atoms connected by four fused rings. Such compounds include synthetic mimetics and analogs of proteins, including partially peptidic, pseudopeptidic, and nonpeptidic molecular entities.

[0050] The term "cortisol" refers to the natural glucocorticoid hormone (also known as hydrocortisone) produced by the zona fasciculata of the adrenal gland.

[0051] The term "glucocorticosteroid" or "glucocorticoid" ("GC") refers to steroid hormones that bind to the glucocorticoid receptor. Glucocorticosteroids are typically characterized as having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-ketol group attached to ring D, with varying degrees of oxygenation or hydroxylation at C-11, C-17, and C-19. See Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

[0052] As used herein, the term "glucocorticoid receptor" ("GR") refers to type II GR, a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also called the cortisol receptor. The term includes isoforms of GR, recombinant GR, and mutant GR.

[0053] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates GC binding to GR or modulates any biological response associated with GR binding to an agonist. For example, GRM acting as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatoma cell line; ECACC, UK). GRM acting as an antagonist, such as mifepristone, decreases the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity is reviewed in the literature, see A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0054] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates GC binding to GR or modulates any biological response associated with GR binding to an agonist. By "selective," it is meant that the drug preferentially binds to GR rather than other nuclear receptors such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). It is preferred that selective glucocorticoid receptor modulators bind to GR with an affinity that is 10 times greater (1 / 10th of the Kd value) than that to MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. In a more preferred embodiment, selective glucocorticoid receptor modulators bind to GR with an affinity that is 100 times greater (1 / 100th of the Kd value) than that to MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. In another embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000-fold greater (1 / 1000th of a Kd value) than its affinity for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. A relacorilant is an SGRM.

[0055] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits GC binding to GR or inhibits any biological response associated with the binding of GR to an agonist. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone. TAT activity is reviewed in the literature, see A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRAs are compounds that have an IC50 (half maximal inhibitory concentration) of less than 10 micromolar. See Example 1 of U.S. Pat. No. 8,859,774.

[0056] As used herein, the term "selective glucocorticoid receptor antagonist" (SGRA) refers to any composition or compound that inhibits GC binding to GR or inhibits any biological response associated with GR binding to an agonist (wherein inhibition is determined with respect to the response in the absence of the compound). By "selective," it is meant that the drug preferentially binds to GR rather than other nuclear receptors such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). Preferably, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 10 times greater (1 / 10th the Kd value) than the affinity for MR, AR, or PR, both AR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. In a more preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 100 times greater (1 / 100th of the Kd value) than its affinity to MR, AR, or PR, both AR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. In another embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 1000 times greater (1 / 1000th of the Kd value) than its affinity to MR, AR, or PR, both AR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. The relacorilant is an SGRA.

[0057] The non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds include compounds containing a fused azadecalin structure (which may also be referred to as a fused azadecalin backbone), compounds containing a heteroaryl-ketone fused azadecalin structure (which may also be referred to as a heteroaryl-ketone fused azadecalin backbone), compounds containing an octahydro fused azadecalin structure (which may also be referred to as an octahydro fused azadecalin backbone), and compounds containing a pyrimidine cyclohexyl backbone.

[0058] Non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds include compounds containing fused azadecalin structures (also called fused azadecalin backbones), compounds containing heteroaryl-ketone fused azadecalin structures (also called heteroaryl-ketone fused azadecalin backbones), compounds containing octahydro fused azadecalin structures (also called octahydro fused azadecalin backbones), and compounds containing pyrimidine cyclohexyl backbones. Exemplary non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds containing fused azadecalin structures include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds containing heteroaryl-ketone fused azadecalin structures include those described in U.S. Patent No. 8,859,774. Exemplary non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds containing octahydro-fused azadecalin structures include those described in U.S. Patent No. 10,047,082. Exemplary non-steroidal GRA compounds, non-steroidal SGRA compounds, non-steroidal GRM compounds, and non-steroidal SGRM compounds containing pyrimidine cyclohexyl backbones include those disclosed in U.S. Patent No. 8,685,973. All patents, patent publications, and patent applications disclosed herein are incorporated herein by reference in their entirety.

[0059] Exemplary heteroaryl-ketone fused azadecalin compounds are described in U.S. Patent No. 8,859,774, U.S. Patent No. 9,273,047, U.S. Patent No. 9,707,223, and U.S. Patent No. 9,956,216, all of which are incorporated herein by reference in their entirety. In one embodiment, the heteroaryl-ketone fused azadecalin GRA is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Example 18 of U.S. Patent No. 8,859,774), also known as "Relacorilant" and "CORT125134", a compound having the following structure: [ka]

[0060] In one embodiment, the heteroaryl-ketone fused azadecalin GRA is the compound having the following structure: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (referred to as "CORT122928"). [ka]

[0061] In one embodiment, the heteroaryl-ketone fused azadecalin GRA is a compound having the following structure: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (also known as "dazcorilant" and "CORT113176"). [ka]

[0062] Glucocorticoid receptor modulators (GRMs) In general, treatment of Cushing's syndrome, Cushing's disease, or liver damage can be provided by administering an effective amount of a glucocorticoid receptor modulator (GRM) of any chemical structure or mechanism of action. In some embodiments, the GRM is mifepristone. In some embodiments, the GRM is a selective GRM (SGRM). In some embodiments, treatment of liver damage can be provided by administering an effective amount of an SGRM. In a preferred embodiment, treatment of Cushing's syndrome, Cushing's disease, or liver damage can be provided by administering an effective amount of a non-steroidal SGRM. Provided herein are exemplary classes of GRMs, particularly exemplary non-steroidal SGRMs, and specific members of such classes. However, one of ordinary skill in the art can readily recognize other related or unrelated GRMs and SGRMs that can be used in the treatment methods described herein.

[0063] In some cases, the nonsteroidal SGRM is relacorilant (CORT125134), i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following structure: [ka]

[0064] Any suitable GRM dose may be used in the methods disclosed herein. The dose of GRM administered may be about 50 milligrams (mg) / day or more, or about 100 mg / day or more, for example, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, or more. In certain embodiments, GRM is administered orally. In some embodiments, GRM is administered in one or more doses. In other words, GRM can be administered in one, two, three, four, five, six, seven, eight, nine, ten, or more doses. In certain embodiments, GRM is administered orally in one, two, three, four, five, six, seven, eight, nine, ten, or more doses.

[0065] A subject may be administered at least once, for example, one or more doses of GRM over a period of 2 to 48 hours. In some embodiments, the GRM is administered as a single dose. In other embodiments, the GRM is administered in two or more doses, for example, two doses, three doses, four doses, five doses, or more, over a period of 2 to 48 hours, for example, 3 hours, 3 hours, 4 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, or 48 hours. In some embodiments, the GRM is administered over a period of 2 to 48 hours, 2 to 36 hours, 2 to 24 hours, 2 to 12 hours, 2 to 8 hours, 8 to 12 hours, 8 to 24 hours, 8 to 36 hours, 8 to 48 hours, 9 to 36 hours, 9 to 24 hours, 9 to 20 hours, 9 to 12 hours, 12 to 48 hours, 12 to 36 hours, 12 to 24 hours, 18 to 48 hours, 18 to 36 hours, 18 to 24 hours, 24 to 36 hours, 24 to 48 hours, 36 to 48 hours, or 42 to 48 hours.

[0066] Single or multiple administrations of the formulation may be administered at a dosage and frequency as needed and tolerated by the patient. It is desirable that the formulation provides a sufficient amount of active agent to effectively treat the disease state. Thus, in certain embodiments, the pharmaceutical formulation for oral administration of GRM is in a daily dose of about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In certain embodiments, the daily dose is about 1.0 to about 100 mg / kg / day, about 5 to about 50 mg / kg / day, about 10 to about 30 mg / kg / day, and about 10 to about 20 mg / kg / day. Lower doses can be used, especially when the drug is administered to an anatomically separated site such as the cerebrospinal fluid (CSF) space, into the bloodstream, into a body cavity, or into the lumen of an organ, as opposed to oral administration. Substantially higher doses can be used for local administration.

[0067] The duration of treatment with a GRM or SGRM to treat Cushing's syndrome, Cushing's disease, or liver damage can vary depending on the severity of symptoms in the subject and the subject's response to the GRM or SGRM. In some embodiments, the GRM or SGRM can be administered for a period of about 1 week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks, and most typically about 9 weeks to 60 weeks. Suitable administration periods 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 administration periods include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, 100 weeks, and 104 weeks. In general, administration of the GRM or SGRM should be continued until a clinically significant reduction or improvement is observed. Treatment with the GRM or SGRM according to the methods disclosed herein may continue for 2 years or longer.

[0068] In some embodiments, administration of the GRM or SGRM is not continuous, but can be stopped for one or more periods, followed by one or more periods during which administration resumes. Suitable times for discontinuing administration 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 100 weeks. Suitable administration suspension periods include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, and 100 weeks.

[0069] Dosing regimens also take into account pharmacokinetic parameters such as rate of absorption, bioavailability, metabolism, and clearance, which are well known in the art (e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; Remington, supra, most recently). Current technology allows the clinician to determine the dosing regimen for the individual patient, GR modulator, and disease or condition being treated.

[0070] SGRMs can be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjuvants that are not effective alone but may contribute to the effectiveness of the active agent.

[0071] In some embodiments, co-administration includes administering the active agent, GRM or SGRM, within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or 24 hours of the second active agent. Co-administration includes administering the two active agents simultaneously, at about the same time (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuncts may be linked or bound to each other.

[0072] After a pharmaceutical composition comprising a GRM discussed herein has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the GRM or SGRM, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

[0073] Pharmaceutical compositions can be provided as salts, which can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, pH range 4.5-5.5, mixed with a buffer prior to use.

[0074] In another embodiment, the composition for treating Cushing's syndrome, Cushing's disease, or liver damage is useful for parenteral administration, such as intravenous (IV) administration or administration into a cavity or lumen of an organ. The formulation for administration generally comprises a solution of the composition dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used include water and Ringer's solution, which is isotonic sodium chloride. In addition, sterile, fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any non-irritating, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and generally free of undesirable matter. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the GRM composition in these formulations can vary widely and is selected primarily based on fluid volumes, viscosities, and body weight, etc., according to the particular mode of administration selected and the needs of the patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous suspension or a sterile injectable oleaginous suspension. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0075] I. Combination Therapy Various combinations of GRMs or SGRMs with other drugs (or combinations of such drugs and compounds) can be used to treat Cushing's syndrome, Cushing's disease, or liver damage in patients. "Combination therapy" or "combination" does not mean that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein. The GRM or SGRM and chemotherapeutic agent can be administered according to the same dosing regimen or different dosing regimens. In some embodiments, the GRM or SGRM and chemotherapeutic agent are administered sequentially in any order for the entire duration or a portion of the treatment period. In some embodiments, the GRM or SGRM and anti-cancer agent are administered simultaneously or nearly simultaneously (e.g., within about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of each other). Non-limiting examples of combination therapy using a GRM or SGRM and a chemotherapeutic agent are as follows, where, for example, the GRM or SGRM is "A" and the anti-cancer agent or compound given as part of the chemotherapy regimen is "B".

[0076] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0077] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0078] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A

[0079] Administration of therapeutic compounds or agents to patients can follow standard protocols for the administration of such compounds, taking into account the toxicity, if any, of the treatment. Surgical intervention can also be applied in combination with the described treatments.

[0080] The method may be combined with other modalities of treatment, such as surgery, radiation, targeted therapy, immunotherapy, or other treatments. EXAMPLES

[0081] The following examples are offered by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.

[0082] Example 1: Liver dysfunction The Phase 1 open-label, multiple-dose study included 18 subjects (aged 18-70 years). Of these subjects, 9 had moderate hepatic impairment (Child-Pugh class B) and 9 were age-, sex-, and weight-matched controls with normal hepatic function.

[0083] Relacorilant was administered at a dose of 300 mg / day under fasting conditions for 10 days. Blood samples for pharmacokinetic (PK) analysis were collected prior to dosing on day 1 and prior to dosing on day 10 until 144 hours after the last dose of study drug (day 16).

[0084] Results: Liver dysfunction test Subjects with moderate hepatic impairment were well matched for age, sex, and weight with a mean total Child-Pugh score of 7.9 (range: 7-9) in subjects with moderate hepatic impairment. Liver function was assessed by measurement of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Decreases in mean liver function tests (LFTs) were observed in patients with moderate hepatic impairment. The mean changes from baseline to day 16 (144 hours after the last dose of Relacorilant) in LFTs are shown in Figure 1.

[0085] Pharmacokinetics (PK) of Relacorilant: Despite the primary hepatic excretion route of Relacorilant, no obvious differences were observed in subjects with moderate hepatic impairment compared with matched controls. Relacorilant exposure (measured by area under the curve and peak plasma concentration) was largely overlapping between both groups.

[0086] Example 2. Relacorilant-Itraconazole Drug-Drug Interaction Study The Phase 1, open-label, fixed-sequence crossover study (NCT03512548) included 25 healthy subjects (ages 18-65 years). Subjects received 300 mg of relacorilant once daily for 10 days, followed by 10 days of both 300 mg of relacorilant once daily and 200 mg of itraconazole once daily. Subjects with AST and / or ALT levels >1.5 times the upper limit of normal (ULN) were excluded from the study.

[0087] A trend towards lower AST was observed in healthy adults treated with relacorilant plus intraconazole (itraconazole is a drug with reported hepatotoxicity). The addition of itraconazole had no relevant effect on the adverse event profile of relacorilant in these subjects. The mean changes in LFTs in these subjects are shown in Figure 2. The right column shows the mean changes in ALT and AST levels in subjects receiving relacorilant alone (from baseline to day 10), and the left column shows the mean changes in ALT and AST levels from baseline to day 11 in subjects receiving relacorilant plus itraconazole.

[0088] Example 3. Phase 2 Cushing's Syndrome Study Thirty-four patients (aged 18-80 years) with endogenous Cushing's syndrome (CS) and impaired glucose tolerance or type 2 diabetes mellitus and / or poorly controlled or untreated hypertension were enrolled in a multicenter, open-label study with two dose groups. Patients with elevated AST or ALT (elevations defined as >3x ULN) were excluded.

[0089] The cases were treated with two dose levels of Relacorilant. The dose in each group was titrated in 50 mg dose increments every 4 weeks. The low-dose group received Relacorilant starting at a dose of 100 mg / day and titrated to a dose of 200 mg / day over the 12-week treatment period. The high-dose group received Relacorilant starting at a dose of 250 mg / day and titrated to a dose of 400 mg / day over the 16-week treatment period.

[0090] Reductions in LFTs were observed in both dose groups, with greater reductions in the high-dose group. Normalization of ALT occurred in 2 of 4 patients with abnormal ALT values ​​at baseline. These results are shown in Figure 3, which shows the mean change in LFTs from baseline to last observation in the efficacy population (n=34). The left-most column shows results from patients in the low-dose group (n=17), the middle column shows results from patients in the high-dose group (n=17), and the right-most column shows the combined results from all patients (n=34).

[0091] The P values ​​shown are the mean changes from baseline to last observation calculated from the Wilcoxon signed rank test. The efficacy population includes all subjects treated with relaxant with post-baseline data.

[0092] Example 4. Ongoing Clinical Trials Figure 4 is a graph of the time course and treatment modality of four ongoing clinical trials of lelacorilant in patients with hypercortisolism. The trials include two Phase 3 trials, GRACE (NCT03697109) and GRADIENT (NCT04308590), a Phase 2 / 3 long-term extension study in patients with CS of all etiologies (NCT03604198), and a Phase 1b adrenocortical carcinoma study (NCT04373265). GRACE is a Phase 3 double-blind randomized treatment withdrawal study of lelacorilant in patients with endogenous hypercortisolism of all etiologies. GRADIENT is a Phase 3 randomized double-blind placebo-controlled study of lelacorilant in patients with cortisol-secreting adrenal adenomas or adrenal hyperplasia. The Phase 2 / 3 extension study is a study of lelacorilant in patients with endogenous hypercortisolism. The phase 1b trial is evaluating relacorilant in combination with pembrolizumab in patients with metastatic adrenocortical carcinoma with hypercortisolism.

[0093] All patents, patent publications, publications, and patent applications cited herein are incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In addition, although the foregoing has been described in some detail by way of illustration and example for clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings herein that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

Claims

1. 1. A method of treating a patient suffering from a disorder selected from liver disorders, Cushing's syndrome, Cushing's disease, cancer, a fungal infection, a bacterial infection, a viral infection, an inflammatory disease or condition, a cardiovascular disease, an endocrine condition, and a renal disease, and combinations thereof, without adverse effects on the patient's liver, comprising: administering to said patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) to treat said disorder or a combination thereof without adverse effects on said patient's liver. The method.

2. 2. The method of claim 1, wherein the liver disorder is fatty liver disease.

3. 3. The method of claim 2, wherein the fatty liver disease is a fatty liver disease selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

4. 4. The method of claim 3, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

5. 4. The method of claim 3, wherein the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

6. 10. The method of claim 1, wherein the patient is suffering from Cushing's syndrome.

7. 10. The method of claim 1, wherein the patient is suffering from Cushing's disease.

8. The method of claim 1, wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

9. 9. The method of claim 8, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 1】

10. 10. The method of any one of claims 1 to 9, further comprising administering to the patient an additional pharmaceutical composition without adverse effects to the patient's liver.

11. 11. The method of claim 10, wherein the additional pharmaceutical composition comprises itraconazole or ketoconazole.

12. 11. The method of claim 10, wherein the additional pharmaceutical composition comprises a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

13. The additional pharmaceutical composition is selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tiza. Nidin, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinaf , ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrane, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benzyl oxalate, , atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidyl,Tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelizine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon 11. The method of claim 10, comprising a drug selected from interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

14. 10. The method of claim 1, wherein the patient is suffering from Cushing's syndrome and liver damage.

15. 10. The method of claim 1, wherein the patient is suffering from Cushing's disease and liver damage.

16. 1. A method of reducing hepatic steatosis in a patient suffering from a disorder selected from a liver disorder, Cushing's syndrome, Cushing's disease, cancer, a fungal infection, a bacterial infection, a viral infection, an inflammatory disease or condition, a cardiovascular disease, an endocrine condition, and a renal disease, and combinations thereof, comprising: administering to said patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) effective to reduce hepatic steatosis in said patient to treat said disorder or a combination thereof without adverse effects on said patient's liver. The method.

17. 17. The method of claim 16, wherein the liver disorder is fatty liver disease.

18. 18. The method of claim 17, wherein the fatty liver disease is a fatty liver disease selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

19. 19. The method of claim 18, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

20. 19. The method of claim 18, wherein the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

21. 17. The method of claim 16, wherein the patient is suffering from Cushing's syndrome.

22. 17. The method of claim 16, wherein the patient is suffering from Cushing's disease.

23. The method of claim 16, wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

24. 24. The method of claim 23, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 2】

25. 25. The method of any one of claims 16-24, further comprising administering to the patient an additional pharmaceutical composition without additional adverse effects on the patient's liver.

26. 26. The method of claim 25, wherein the additional pharmaceutical composition comprises itraconazole or ketoconazole.

27. 26. The method of claim 25, wherein the additional pharmaceutical composition comprises a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

28. The additional pharmaceutical composition is selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tiza. Nidin, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinaf , ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrane, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benzyl oxalate, , atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidyl,Tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelizine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon 26. The method of claim 25, comprising a drug selected from interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

29. 17. The method of claim 16, wherein the patient is suffering from Cushing's syndrome and liver damage.

30. 17. The method of claim 16, wherein the patient is suffering from Cushing's disease and liver damage.

31. 1. A method for reducing or preventing hepatotoxicity in a patient receiving a drug that can cause hepatotoxicity, comprising: administering to the patient, in addition to the drug capable of causing hepatotoxicity, an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM); The method.

32. 32. The method of claim 31, wherein the patient is receiving a drug that can cause liver toxicity and is then administered the SGRM.

33. 32. The method of claim 31, wherein the patient is administered the SGRM and then is administered the drug that can cause liver toxicity.

34. 32. The method of claim 31 , wherein the patient is suffering from fatty liver disease.

35. 35. The method of claim 34, wherein the fatty liver disease is a fatty liver disease selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

36. 36. The method of claim 35, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

37. 32. The method of claim 31, wherein the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

38. 32. The method of claim 31, wherein the patient is suffering from Cushing's syndrome.

39. 32. The method of claim 31 , wherein the patient is suffering from Cushing's disease.

40. The method according to any one of claims 31 to 39, wherein the non-steroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

41. 41. The method of claim 40, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 3】

42. 42. The method of any one of claims 31 to 41, wherein the drug that may cause hepatotoxicity is a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

43. The drug capable of causing liver toxicity is mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, cephalosporin, tizanidine, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, Terbinafine, ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrane, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisxocin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benzalone Zyiodarone, atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir,Suloctidil, tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon The method according to any one of claims 31 to 41, wherein the drug is selected from the group consisting of interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alpha-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

44. The method according to any one of claims 31 to 41, wherein the drug capable of causing hepatotoxicity is ketoconazole.

45. The method according to any one of claims 31 to 41, wherein the drug capable of causing hepatotoxicity is itraconazole.

46. The method of any one of claims 31 to 45, wherein the patient is suffering from Cushing's syndrome and liver damage.

47. 47. The method of any one of claims 31 to 46, wherein the patient is suffering from Cushing's disease and liver damage.

48. 1. A method of treating a patient receiving a drug that can cause hepatotoxicity without adverse effects on the patient's liver, comprising: administering to said patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) to treat said patient receiving a drug that can cause hepatotoxicity without adverse effects on said patient's liver. The method.

49. 49. The method of claim 48, wherein the patient is administered a drug that may cause liver toxicity and is then administered the SGRM.

50. 49. The method of claim 48, wherein the patient is administered the SGRM and then is administered the drug that may cause liver toxicity.

51. 49. The method of claim 48, wherein the patient is suffering from fatty liver disease.

52. 52. The method of claim 51, wherein the fatty liver disease is a fatty liver disease selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

53. 53. The method of claim 52, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

54. 54. The method of claim 53, wherein the nonalcoholic fatty liver disease (NAFLD) is nonalcoholic steatohepatitis (NASH) or nonalcoholic cirrhosis.

55. 49. The method of claim 48, wherein the patient is suffering from Cushing's syndrome.

56. 49. The method of claim 48, wherein the patient is suffering from Cushing's disease.

57. The method of any one of claims 48 to 56, wherein the non-steroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

58. 58. The method of claim 57, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 4】

59. 59. The method of any one of claims 48 to 58, wherein the drug that may cause hepatotoxicity is a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

60. The drug capable of causing liver toxicity is mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, cephalosporin, tizanidine, tolcapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, Terbinafine, ticrynafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrane, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisxocin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benzalone Zyiodarone, atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir,Suloctidil, tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon The method according to any one of claims 48 to 58, wherein the drug is selected from the group consisting of interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

61. The method according to any one of claims 48 to 58, wherein the drug capable of causing hepatotoxicity is ketoconazole.

62. The method according to any one of claims 48 to 58, wherein the drug capable of causing hepatotoxicity is itraconazole.

63. 63. The method of any one of claims 48 to 62, wherein the patient is suffering from Cushing's syndrome and liver damage.

64. 64. The method of any one of claims 48 to 63, wherein the patient is suffering from Cushing's disease and liver damage.

65. 65. The method of any one of claims 48 to 64, wherein the non-steroidal SGRM is a compound comprising a heteroaryl-ketone fused azadecalin structure.

66. 66. The method of claim 65, wherein the non-steroidal SGRM is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 5】

67. 67. The method of any one of claims 48-66, wherein the patient has excessive blood levels of the liver enzyme alanine aminotransferase, and administration of the non-steroidal SGRM compound does not increase said blood levels of the liver enzyme.

68. 68. The method of any one of claims 48-67, wherein the patient has excessive blood levels of the liver enzyme aspartate aminotransferase, and administration of the non-steroidal SGRM compound does not increase said blood levels of the liver enzyme.

69. 69. The method of any one of claims 48 to 68, wherein the patient has been administered a drug selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

70. The patient is receiving mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, thrombin ... Lucapone, valproic acid, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, Clinafen, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacrane, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxocin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benziodarone, Atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fialuridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidyl,Tolrestat, fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaprolclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, The method of any one of claims 48 to 68, wherein the patient has been administered a drug selected from interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

71. The method of any one of claims 48 to 68, wherein the patient has been administered ketoconazole.

72. The method of any one of claims 48 to 68, wherein the patient has been administered itraconazole.

73. 1. Use of a nonsteroidal selective glucocorticoid receptor modulator for treating a disorder selected from Cushing's syndrome, Cushing's disease, and fatty liver disease without adverse effects on liver enzyme levels or liver function, comprising: Use with drugs that can cause hepatotoxicity The above uses.

74. 74. The use of claim 73, wherein the disorder is Cushing's syndrome.

75. 74. The use of claim 73, wherein the disorder is Cushing's disease.

76. 74. The use of claim 73, wherein the disorder is fatty liver disease.

77. 77. The use of claim 76, wherein the fatty liver disease is selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

78. 78. The use of claim 77, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

79. 78. The use of claim 77, wherein the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

80. The use according to any one of claims 73 to 79, wherein the non-steroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

81. 81. The use of claim 80, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 6】

82. 82. The use of any one of claims 73 to 81 comprising use in conjunction with a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

83. Mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, tolcapone, valproate, Progesterone, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, ticrynafen, Trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacran, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benziodarone, atomoxetine, Chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon alpha-2b, interferon alpha-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidil, tolrestat,Fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelizine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaproclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon beta-2a, interferon beta-1b ... Use according to any one of claims 73 to 81, comprising use with a drug selected from feron alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

84. 82. Use according to any one of claims 73 to 81, comprising use together with ketoconazole.

85. 82. Use according to any one of claims 73 to 81, comprising use together with itraconazole.

86. 1. Use of a nonsteroidal selective glucocorticoid receptor modulator in the manufacture of a medicament for treating a disorder selected from Cushing's syndrome, Cushing's disease, and fatty liver disease without adverse effects on liver enzyme levels or liver function, comprising: Use with drugs that can cause hepatotoxicity The above uses.

87. 87. The use of claim 86, wherein the disorder is Cushing's syndrome.

88. 87. The use of claim 86, wherein the disorder is Cushing's disease.

89. 87. The use of claim 86, wherein the disorder is fatty liver disease.

90. 90. The use of claim 89, wherein the fatty liver disease is selected from alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD).

91. 91. The use of claim 90, wherein the alcohol-related liver disease (ARLD) is alcoholic fatty liver disease (AFL), alcoholic steatohepatitis (ASH), or alcoholic cirrhosis.

92. 91. The use of claim 90, wherein the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

93. The use according to any one of claims 87 to 92, wherein the non-steroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl-ketone fused azadecalin structure.

94. 94. The use of claim 93, wherein the nonsteroidal selective glucocorticoid receptor modulator is relacorilant, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following chemical formula: 【Chemistry 7】

95. 95. The use of any one of claims 87 to 94, comprising use in conjunction with a CYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.

96. Mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, tolcapone, valproate, Progesterone, zidovudine, troglitazone, fluconazole, itraconazole, clomipramine, clarithromycin, testosterone, etodolac, pemoline, nevirapine, benzbromarone, busulfan, disulfiram, isoniazid, nimesulide, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, ticrynafen, Trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, aplaviroc, clomacran, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenol isatin, fisoxacin, paflysin, phenoxypropazine, oxandrolone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzalone, benziodarone, atomoxetine, Chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclophenyl, didanosine, interferon alpha-2b, interferon alpha-2a, recombinant, droxicam, ethambutol, infliximab, exifon, fiaruridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, suloctidil, tolrestat,Fenclozic acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, farnidamole, zimelizine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaproclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin, oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon beta-2a, interferon beta-1b ... Use according to any one of claims 87 to 94, comprising use with a drug selected from feron alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

97. 95. The use according to any one of claims 87 to 94, comprising use together with ketoconazole.

98. 95. Use according to any one of claims 87 to 94, comprising use together with itraconazole.

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