Methods of treating Cushing's syndrome and liver disease and reducing hepatotoxicity of other drugs administered by patients

Abstract

Disclosed are methods and uses for treating a subject having a condition selected from liver disease, Cushing's syndrome or Cushing's disease, cancer, infection, inflammation, cardiovascular, endocrine or kidney disease, and combinations thereof, or other disease that may thus be administered a drug that may cause hepatotoxicity, the methods and uses having no adverse effects on the liver. The liver diseases comprise fatty liver diseases, high-level liver enzyme can be effectively reduced, and good safety is achieved. The methods and uses include administering to a subject an effective amount of a selective non-steroidal glucocorticoid receptor modulator, such as relacan, including methods and uses for use in combination with other drugs, without adversely affecting liver enzyme levels or liver function. In embodiments, another drug may be a drug that may cause hepatotoxicity, such as a drug that inhibits the CYP3A enzyme, such as itraconazole or ketoconazole.

Description

Background Art

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

[0002] Elimination of administered relazoline occurs primarily through the liver (via CYP3A and carbonyl reductase). Relazoline is a strong CYP3A4 inhibitor, but its administration does not result in clinically significant inhibition of CYP2C8 or CYP2C9. Therefore, it appears to interact with the liver and other enzymes.

[0003] However, many drugs that affect the glucocorticoid receptor (GR) or cortisol levels or cortisol effects have significant effects on the liver. Many patients take drugs that may cause hepatotoxicity. For example, some drugs such as ketoconazole and itraconazole may cause hepatotoxicity. However, some patients may take drugs that may cause hepatotoxicity as well as drugs that affect the GR. For example, high cortisol levels (common in Cushing's syndrome) may cause or are often accompanied by high levels of liver fat, high levels of liver enzymes (such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc.), hepatic steatohepatitis (NASH), and other liver diseases. Such high cortisol levels can be treated with drugs that affect the GR.

[0004] Liver diseases can be divided into different disease groups such as alcoholic fatty liver disease (AFLD), nonalcoholic fatty liver disease (NAFLD), drug- or alcohol-related liver disease, viral diseases, immune-mediated liver disease, metabolic liver disease, and complications related to liver insufficiency and / or liver transplantation. Nonalcoholic fatty liver disease is a common liver disease with histological features similar to alcoholic fatty liver disease and occurs in individuals who consume little or no alcohol. Fatty liver disease is due to abnormal retention of lipids (fats) within hepatocytes. Effective treatments for AFLD and NAFLD remain inadequate. To date, no therapeutic agents have been established for these patients. Novel treatment options are needed for the management of fatty liver disease. New treatment options are needed for patients who require treatment with medications that may cause hepatotoxicity and medications that affect the GR. Summary of the invention

[0005] The present method provides an improved method for administering a selective glucocorticoid receptor modulator (SGRM) and a drug that may cause hepatotoxicity to a patient in need. A novel method for treating Cushing's syndrome and Cushing's disease with good liver safety is disclosed herein. Also disclosed herein are novel methods for treating liver diseases including fatty liver disease, reducing high levels of liver enzymes and other treatments, all of which have good liver safety. The applicant discloses here that the SGRM relacolan has good liver safety after being administered to healthy and liver-impaired adults and patients with Cushing's syndrome. The method includes administering an effective amount of relacolan to the subject without adversely affecting liver enzyme levels or liver function. In an embodiment, the method includes administering an effective amount of relacolan in combination with another drug to the subject without adversely affecting liver enzyme levels or liver function. In an embodiment, the method includes a method for reducing or preventing hepatotoxicity in patients receiving drugs that may cause hepatotoxicity, the method including also administering to the patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) in addition to the drug that may cause hepatotoxicity. In an embodiment, the patient is receiving a drug that may cause hepatotoxicity and then receives an SGRM. In an embodiment, the patient is receiving an SGRM and then receives a drug that may cause hepatotoxicity. In an embodiment, another drug may be a drug that can inhibit CYP3A enzymes (including CYP3A4 enzymes), such as itraconazole or ketoconazole. In an embodiment, the method includes reducing the hepatic steatosis of a patient suffering from liver disease, Cushing's syndrome, Cushing's disease, or a combination thereof, and the method is by giving the patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) that effectively reduces the hepatic steatosis of the patient. In an embodiment, the method includes co-administering an effective amount of relaconazole when the patient is receiving or is about to receive a drug with known hepatotoxicity (e.g., itraconazole, ketoconazole or other CYP3A inhibitors), to effectively reduce, prevent or eliminate the hepatotoxicity of the drug with known hepatotoxicity.

[0006] Relaquelin is a heteroaryl ketone-fused azadecalin compound disclosed and described in Example 18 of U.S. Pat. No. 8,859,774, the entire contents of which are hereby incorporated by reference. The chemical name of Relaquelin 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; it has the following structure:

[0007] The applicant has found and disclosed herein that relacolan has good liver safety, including a trend of improvement in liver function tests (LFTs) in healthy volunteers and patients with normal and impaired liver function. The applicant has found and disclosed herein that relacolan can be safely administered to patients with moderately impaired liver function as well as patients with normal liver function. Therefore, SGRMs such as relacolan can be administered to patients with impaired liver function in the same manner, dosage and frequency of administration as those administered to patients with normal liver function. These findings in patients with impaired liver function support the use of relacolan to treat patients with Cushing's syndrome and Cushing's disease with moderately impaired liver function without adjusting the dose of relacolan (compared to the dose used for patients without moderately impaired liver function). The findings in patients with liver damage also support the use of relacolan to treat patients with liver disease with moderate liver damage without adjusting the dose of relacolan (compared to the dose used for patients without liver disease). Relacolan can be administered in the treatment of liver diseases, including, for example, fatty liver diseases. For example, fatty liver diseases include alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and other liver diseases. SGRMs such as relazoline can be administered to patients with cancer, fungal infections, or other conditions for which potentially hepatotoxic drugs may be coadministered without adjusting the relazoline dose compared to the dose used in the absence of the potentially hepatotoxic drug.

[0008] Relaquelan can be administered orally or by other suitable means. In the studies disclosed herein, Relaquelan is orally administered at a dose of 100 mg to 400 mg per day. Relaquelan can be administered once a day, or twice, three times, or other times a day.

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

[0010] The present method provides an improved method for treating patients receiving SGRMs and drugs that may cause hepatotoxicity in the patient. The present method provides an improved method for treating Cushing's syndrome, Cushing's disease, and liver diseases including fatty liver, elevated liver enzyme levels, and other liver diseases. The present method provides an improved method for reducing hepatic steatosis in patients with liver disease, Cushing's syndrome, Cushing's disease, or a combination thereof. The present method provides an improved method for reducing, preventing, or eliminating the hepatotoxicity of drugs with known hepatotoxicity by administering an SGRM (e.g., relaquinoxaline) in combination with a known hepatotoxic drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Results from a liver injury study are shown.

[0012] Figure 2 Results of a drug interaction study (relaconazole-itraconazole) are shown.

[0013] Figure 3 Results from a phase 2 Cushing's syndrome study are shown.

[0014] Figure 4 The study design of the ongoing clinical study is shown. DETAILED DESCRIPTION

[0015] Disclosed are methods and uses for treating subjects suffering from conditions selected from liver disease, Cushing's syndrome or Cushing's disease, cancer, infection, inflammation, cardiovascular, endocrine or renal disease and combinations thereof, or other diseases for which drugs that may cause hepatotoxicity may be administered, and the methods and uses have no adverse effects on the liver. Such liver diseases include fatty liver disease, which can effectively reduce high levels of liver enzymes and have good safety. The methods and uses include administering to the subject an effective amount of a selective nonsteroidal glucocorticoid receptor modulator, such as relaconazole, including methods and uses used in combination with other drugs, without adverse effects on liver enzyme levels or liver function. In an embodiment, the other drug may be a drug that may cause hepatotoxicity, such as a drug that inhibits CYP3A enzymes, such as itraconazole or ketoconazole.

[0016] Therefore, applicants disclose herein an improved method for administering a non-steroidal selective glucocorticoid receptor modulator (SGRM) to a patient who may receive another drug that may cause hepatotoxicity without adversely affecting the patient's liver. For example, the SGRM may be a heteroaryl ketone fused azadecalin compound, and in an embodiment may be relaquinone. Applicants disclose herein that an SGRM (e.g., relaquinone) can be administered to a patient with a normal liver or a patient with moderately impaired liver function at the same dose. Applicants disclose herein that an SGRM (e.g., relaquinone) can be administered to a patient who has not received a drug that may cause hepatotoxicity or a patient who has received or will receive a drug that may cause hepatotoxicity at the same dose. An SGRM (e.g., relaquinone) can be administered to a patient with impaired liver function in the same manner, dose, and frequency of administration as a patient with normal liver function.

[0017] The methods disclosed herein include treating patients who are receiving or are about to receive drugs that may cause hepatotoxicity and will not adversely affect the patient's liver, and the method includes administering to the patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) to treat the patient who is receiving or is about to receive the drug that may cause hepatotoxicity, and will not adversely affect the patient's liver. In an embodiment, the method includes a method in which the patient is receiving a drug that may cause hepatotoxicity and then administering the SGRM. In an embodiment, the method includes a method in which the patient is receiving the SGRM and then administering the drug that may cause hepatotoxicity. In an embodiment, the SGRM is relacolan. In an embodiment, the patient suffers from Cushing's syndrome, Cushing's disease, liver disease, cancer, or other diseases in which the patient may be administered drugs that may cause hepatotoxicity.

[0018] Applicants disclose herein the use of SGRMs (e.g., relaquent) for reducing or preventing hepatotoxicity in patients who are receiving or are about to receive drugs that may cause hepatotoxicity, the use comprising using an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) (before, during, or after administration) in conjunction with a drug that may cause hepatotoxicity. In an embodiment, the patient has received a drug that may cause hepatotoxicity and then uses the SGRM. In an embodiment, the patient has received an SGRM and then uses a drug that may cause hepatotoxicity. In an embodiment, the SGRM is relaquent.

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

[0020] Applicants disclose herein a method of treating a patient suffering from Cushing's syndrome, Cushing's disease, liver disease, or cancer, or a combination thereof, without adversely affecting the patient's liver, the method comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the liver disease or Cushing's syndrome without adversely affecting the patient's liver. Applicants disclose herein a method of treating a patient suffering from Cushing's syndrome, Cushing's disease, liver disease, cancer, fungal infection, bacterial infection, viral infection, inflammatory disease or condition, cardiovascular disease, endocrine disease, kidney disease, or a combination thereof, without adversely affecting the patient's liver, the method comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the disease without adversely affecting the patient's liver.

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

[0022] The applicant discloses a method for reducing or preventing hepatotoxicity in patients receiving drugs that may cause hepatotoxicity, the method comprising administering to the patient an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) in addition to the drug that may cause hepatotoxicity. Many different drugs are associated with hepatotoxicity (see, for example, Bjornsson et al., Int. J. Mol. Sci. 2016, 17, 224–230; and Chen et al., Drug Discov Today. 2016, 21 (4): 648-653). A drug ranking list (sorted by severity of liver injury) entitled "Drug-Induced Liver Injury Ranking (DILIrank) Dataset" can be downloaded from the U.S. Food and Drug Administration website "fda.gov". The DILIrank data set contains 1,036 FDA-approved drugs, which are divided into three categories according to their likelihood of causing drug-induced liver injury (DILI), while the hepatotoxicity data of the fourth group of drugs are unclear. Of the 1036 drugs discussed, 192 were considered to be the most relevant, 278 were less relevant than the most relevant drugs; for 254 drugs, the analysis results were unclear, and 312 of the 1036 drugs were found to be not associated with DILI.

[0023] In an embodiment, the drug that may cause hepatotoxicity is a drug listed in the DILIrank dataset. In an embodiment, the drug that may cause hepatotoxicity is a drug identified as "Most-DILI-Concern" or "Less-DILI-Concern" in the DILIrank dataset. In an embodiment, the drug that may cause hepatotoxicity is a drug identified as "Most-DILI-Concern" in the DILIrank dataset. The 192 drugs most relevant to DILI in the DILIrank dataset are: mercaptopurine, indomethacin, phenytoin, rifampin, abacavir, allopurinol, amineptine, amiodarone, bicalutamide, chlorzoxazone, dactinomycin, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, mefenamic acid, and phenoxyethanol. acid, methyldopa, nefazodone, nitrofurantoin, perhexiline, propylthiouracil, stavudine, sulindac, tamoxifen, tizanidine, tolcapone, valproic acid,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 sodiumsodium), lumiracoxib, tasosartan, oxyphenisatin, tilbroquinol, alclofenac, apraviroc, clomacran, dermatan, isaxonine, pipamazine, pralnacasan, sulfacarbamide, triacetyldiphenolisatin, fiduxosin, pafuraidine, phenoxypropazine, oxandrolone, androlone, acarbose, alpidem, bexarotene, voriconazole, bendazac, benzarone, benziodarone, atomoxetine, chlormezanone, erlotinib, cinchophen, tipranavir, clometacin, sorafenib, darunavir, cyclofenil, didanosine, interferon alfa-2b, interferon alfa-2a,alfa-2a, recombinant, droxicam, ethambutol, infliximab, exifone, fialuridine, fipexide, fosphenytoin, gemcitabine, levofloxacin, mebanazine, moxisylyte, nialamide, nilutamide, niperotidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sulcotidil, tolrestat, fenclozic acid acid, ebrotidine, nitrefazole, tetrabamate, xenazoic acid, zafirlukast, falnidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, mepazine, lapatinib, alaproclate, orlistat, sitaxsentan, carbamazepine, felbamate, ciprofloxacin n), oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1bbeta-1b), interferon beta-1a, interferon alfacon-1, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid acid, zileuton, acitretin, natalizumab, papaverine, gemfibrozil, ticlopidine, exemestane, gefitinib, eltrombopag olamine, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

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

[0025] In an embodiment, the patient has Cushing's syndrome. In an embodiment, the patient has Cushing's syndrome and liver disease.

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

[0027] The non-steroidal selective glucocorticoid receptor modulator can be a compound comprising a heteroaryl ketone fused azadecalin structure. In an embodiment, the non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

[0028] The methods disclosed herein also include administering other pharmaceutical compositions to the patient without causing other adverse effects on the patient's liver. In an embodiment, the other pharmaceutical compositions include itraconazole or ketoconazole. In an embodiment, the other pharmaceutical compositions include CYP3A inhibitors. In an embodiment, the other pharmaceutical compositions include CYP3A inhibitors selected from the following: ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranavir, paritaprevir and voriconazole.In an embodiment, the other pharmaceutical composition comprises a drug selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amipheptanate, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methamine, 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, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cinchofen, titin Pramvir, clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, epoxetine, fealuridine, phepivacetide, fosphenytoin, gemcitabine, levofloxacin, mebanazone, basilamide, niacinamide, nilutamide, niperidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, toristastat, fenclorac, bromitidine, nitrazol, tetracarbamate, benzylfenamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, meropenem, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin , oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

[0029] Current clinical studies of relacolan for patients with endogenous hypercortisolism (e.g., Cushing's syndrome or Cushing's disease) include liver function test (LFT) assessments. In an embodiment, LFT assessments include measuring alanine aminotransferase (ALT) levels, measuring aspartate aminotransferase (AST) levels, or both. LFT assessments may also include magnetic resonance imaging (MRI) of the liver, computer-assisted tomography (CAT) images of the liver, liver biopsy and other tests. Other clinical parameters of the patient may be determined, including, for example, blood pressure, blood sugar levels, Hb1Ac levels, blood potassium levels, body weight, glucose tolerance measurements, insulin levels, blood coagulation measurements, patient cognitive function, patient mood, quality of life and other measurements. b. Definition

[0030] Cushing's syndrome is a disorder caused by excessive production of the glucocorticoid cortisol by the adrenal cortex. The condition is usually due to the presence of a tumor or hyperplasia, which leads to uncontrolled secretion of adrenocorticotropic hormone (ACTH). Uncontrolled ACTH secretion in turn induces the adrenal glands to secrete excessive amounts of cortisol. Cortisol normally participates in a negative feedback loop, in which high levels of cortisol inhibit the secretion of ACTH and cortisol. However, in Cushing's syndrome, this negative regulation is ineffective or absent, resulting in chronic hypercortisolemia.

[0031] Liver enzymes are essential for the utilization of food, the maintenance of homeostasis in organisms (including human patients), and may play an important role in the metabolism of drug compounds given to patients. Such liver enzymes may also be present in other tissues, CYP enzymes such as CYP2C8, CYP2C9, CYP3A4 and other CYP enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST). For example, such enzymes are discussed in U.S. Patent Nos. 10,195,214 and 11,285,145, which are incorporated herein by reference in their entirety.

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

[0033] As used herein, the terms "potentially hepatotoxic drugs," "potentially hepatotoxic agents," "hepatotoxic drugs," and "hepatotoxic agents" refer to drugs and agents that may cause liver damage and / or toxic liver disease. For example, such drugs and agents may be, but are not limited to, drugs, herbs, solvents, poisonous foods (e.g., poisonous mushrooms), and other agents that may damage the liver.

[0034] Drugs that may cause hepatotoxicity include, but are not limited to, mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amitriptyline, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipranvir, Clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, cyclopentolone, fealuridine, phenytoin, gemcitabine, levofloxacin, mebanazone, pyrimidine, niacinamide, nilutamide, niperidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, toristastat, fenclorac, bromitidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, maceprazine, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, hydroxy Methedrolone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

[0035] As used herein, the terms "liver disease" and "hepatic disease" refer to a disease or condition of the liver. Liver disease includes, but is not limited to, fatty liver disease, alcohol-related liver disease, nonalcoholic fatty liver disease, hepatitis, and other liver diseases. For example, liver disease is discussed in U.S. Pat. No. 10,238,659, which is incorporated herein by reference in its entirety.

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

[0037] "Alcohol-related liver disease" or "ARLD" refers to liver disease caused in whole or in part by or attributable to excessive alcohol consumption. There are four main 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 intake of more than about 15-30 g / day of ethanol.

[0038] Alcohol consumption depends on multiple hereditary and non-hereditary factors to the physiological impact of liver function or disease, and these factors can change the clinical course of individual susceptibility and ARLD.Therefore, in some patients, ARLD can develop when the alcohol consumption rate is low, including consumption of at least about 12g / day, 15g / day, 20g / day, 25g / day or more.In addition, it should be understood that in some patients, the estimated value of daily alcohol consumption is a mean value, including the period of drinking a lot of alcohol and a small amount or the period of not drinking alcohol.This type of mean value can include the mean value of alcohol consumption in at least about one week, two weeks, one month, three months, six months, nine months, one year, 2 years, 3 years or 4 years or longer time. In certain instances, the determination of whether the liver dysfunction is ARLD is based on a variety of factors, including, but not limited to: the amount and type of alcoholic beverages consumed (e.g., beer or liquor); the duration of alcohol abuse; drinking behavior patterns (e.g., binge drinking, drinking without food, etc.); sex; race; comorbid conditions, such as metabolic syndrome or diabetes, iron overload, or infection with hepatitis viruses, genetic markers; family history; liver enzyme levels; proinflammatory cytokine levels; gene or protein expression analysis; or histopathological examination of liver tissue or cells.

[0039] “Liver disease not associated with excessive alcohol intake” is a type of liver disease that is different from ARLD. Therefore, this type of disease refers to a range of liver diseases that are not caused by alcohol consumption. For example, hepatitis may be caused by a viral infection. Liver diseases caused by excessive alcohol consumption and other factors are considered ARLD, not liver diseases not associated with excessive alcohol intake. Conversely, liver diseases that are only exacerbated by excessive alcohol consumption are considered liver diseases not associated with excessive alcohol intake.

[0040] "Non-alcoholic fatty liver disease" or "NAFLD" refers to fatty liver disease characterized by the presence of fat (lipids) in the liver without significant inflammation or hepatotoxicity. NAFLD may progress to non-alcoholic steatohepatitis and then to irreversible advanced liver scarring or cirrhosis.

[0041] "Non-alcoholic steatohepatitis" or "NASH" refers to a fatty liver disease that is similar to alcoholic liver disease, but occurs in people who drink little or no alcohol. The main features of NASH are fat in the liver, as well as inflammation and damage. NASH can lead to cirrhosis, in which the liver becomes permanently damaged and scarred and is no longer able to function properly. The differential diagnosis of NASH from NAFLD can be determined by a liver biopsy.

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

[0043] As used herein, the terms "administering / administering", "dosing", "administered", or "administered" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. Administration can be by oral administration (i.e., the subject receives the compound or composition through the mouth in the form of a pill, capsule, liquid, or other form suitable for administration through the mouth. Oral administration can be buccal (wherein the compound or composition is contained in the mouth, such as under the tongue, and absorbed therein). Administration can be by injection, i.e., delivering the compound or composition by a needle, microneedle, pressure syringe, or other means of piercing the skin or forcing the compound or composition through the subject's skin. Injection can be intravenous (i.e., into a vein), intraarterial (i.e., into an artery), intraperitoneal (i.e., into the peritoneum), intramuscular (i.e., into a muscle), or by other injection routes. Routes of administration can also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption into 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 the amount of a pharmaceutical agent that effectively treats, eliminates or alleviates at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to the amount of a functional agent or pharmaceutical composition that can be used to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any test method known in the art. The effective amount may be an amount that effectively causes an anti-tumor response. For the purposes of this disclosure, an effective amount of SGRM or an effective amount of a chemotherapeutic agent is an amount that treats liver disease or brings about other desired beneficial clinical results associated with the treatment of liver disease.

[0045] As used herein, the term "combination / combination therapy" refers to administering at least two agents to a subject to treat a disease. The two agents can be administered simultaneously or sequentially in any order throughout the treatment period or a portion of the treatment period. At least two agents can be administered according to the same or different dosing schedules. In some cases, one agent is administered according to a predetermined schedule and another agent is administered intermittently. In some cases, two agents are administered intermittently. In some embodiments, one agent (e.g., SGRM) is administered daily, while another agent, e.g., a chemotherapeutic agent, is administered every two, three, or four days.

[0046] As used herein, the term "compound" is used to refer to a molecular moiety having a unique, identifiable chemical structure. A molecular moiety ("compound") can exist in a free form, in which it is not associated with other molecules. A compound can also exist as part of a larger aggregate, in which it is associated with one or more other molecules, but still retains its chemical characteristics. A solvate is an example of such an associated form, in which a molecular moiety ("compound") having a defined chemical structure is associated with solvent molecules. A hydrate is a solvate in which the associated solvent is water. Reference to a "compound" refers to the molecular moiety (having the described structure) itself, whether it exists in a free form or an associated form.

[0047] As used herein, the term "composition" is meant to encompass products comprising specified ingredients (e.g., compounds disclosed herein), as well as specified amounts of tautomers, derivatives, analogs, stereoisomers, polymorphs, deuterated substances, pharmaceutically acceptable salts, esters, ethers, metabolites, isomer mixtures, pharmaceutically acceptable solvates and pharmaceutically acceptable compositions thereof, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. The pharmaceutical compositions discussed herein are intended to encompass any composition made by mixing the compounds discussed and a pharmaceutically acceptable carrier thereof.

[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 agents and absorption delay agents, etc., that are compatible with drug administration. These terms refer to substances that help to administer the active agent to the subject and be absorbed by the subject, and can be included in the pharmaceutical composition without causing significant adverse toxic effects to the patient. Unless any conventional medium or medicament is incompatible with the active compound, it is considered to be used in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavoring agents and pigments, etc. Those of ordinary skill in the art will recognize that other pharmaceutical excipients may also be useful.

[0049] As used herein, the phrase "non-steroidal skeleton" in the context of SGRM refers to an SGRM that does not have structural homology with Cortisol or is not a modified Cortisol, the steroidal skeleton of which contains 17 carbon atoms bonded in four fused rings. Such compounds include synthetic mimetics and analogs of proteins, including partial peptides, pseudopeptides and non-peptide molecular entities.

[0050] The term "Cortisol" refers to a naturally occurring glucocorticoid (also known as hydrocortisone) produced by the zona fasciculata of the adrenal glands.

[0051] The term "glucocorticoid" or "glucocorticoid (GC)" refers to a steroid hormone that is bound to a glucocorticoid receptor. The general characteristics of glucocorticoids are that they have 21 carbon atoms, α in ring A, β-unsaturated ketones, α-keto alcohol groups connected to ring D. They differ in the degree of oxidation and hydroxylation of C-11, C-17 and C-19 (Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," Biochemistry, Daisy et al. (eds.), 1989, p. 567).

[0052] As used herein, the term "glucocorticoid receptor (GR)" refers to type II GR, which is an intracellular receptor that specifically binds to Cortisol and / or Cortisol analogs such as dexamethasone (see, e.g., Turner and Muller, J. Mol. Endocrinol. 2005 Oct. 1 35(2):283-292). The glucocorticoid receptor is also known as the Cortisol receptor. The term includes isomers of GR, recombinant GR, and mutant GR.

[0053] The term "glucocorticoid receptor modulator (GRM)" refers to any compound that regulates the binding of GC to GR or regulates any biological response associated with the binding of GR to an agonist. For example, GRMs (such as dexamethasone) as agonists can increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRMs (such as mifepristone) as antagonists can reduce the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be detected as described in the literature: 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 and agonist binding. By "selective", the drug preferentially binds to GR rather than other nuclear receptors, such as progesterone receptor (PR), mineralocorticoid receptor (MR) or androgen receptor (AR). Preferably, the affinity of the selective glucocorticoid receptor modulator to bind to GR is 10 times the affinity of its binding to the MR, AR or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR and PR (K d In a more preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity 100 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR. d In another embodiment, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000 times greater than its affinity for binding to MR, AR or PR, MR and PR, MR and AR, AR and PR, or MR, AR and PR (K d 1 / 1000 of its value). Rilacoln is SGRM.

[0055] A "glucocorticoid receptor antagonist" (GRA) is any compound that inhibits the binding of GC to GR, or any biological response associated with the binding of GR to an agonist. Thus, GR antagonists can be identified by measuring the ability of the compound to inhibit the action of dexamethasone. TAT activity can be detected as described in the literature: A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRA is an IC 50 (half maximal inhibitory concentration) of less than 10 micromolar compounds. See Example 1 of U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference.

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

[0057] Non-steroidal GRA, SGRA, GRM and SGRM compounds include compounds containing a fused azadecalin structure (also referred to as a fused azadecalin skeleton), compounds containing a heteroaryl-keto fused azadecalin structure (also referred to as a heteroaryl-keto fused azadecalin skeleton), compounds containing an octahydro-fused azadecalin structure (also referred to as an octahydro-fused azadecalin skeleton), and compounds containing a pyrimidine cyclohexyl backbone.

[0058] Nonsteroidal GRA, SGRA, GRM and SGRM compounds include compounds containing fused azadecalin structures (also referred to as fused azadecalin skeletons), compounds containing heteroaryl-ketone fused azadecalin structures (also referred to as heteroaryl-ketone fused azadecalin skeletons), compounds containing octahydro-fused and azadecalin structures (also referred to as octahydro-fused azadecalin skeletons), and compounds containing pyrimidine cyclohexyl backbones. Exemplary nonsteroidal GRA, SGRA, GRM and SGRM compounds containing fused azadecalin structures include those described in U.S. Pat. Nos. 7,928,237 and 8,461,172. Exemplary nonsteroidal GRA, SGRA, GRM and SGRM compounds containing heteroaryl ketone fused azadecalin structures include those described in U.S. Pat. No. 8,859,774. Exemplary nonsteroidal GRA, SGRA, GRM and SGRM compounds containing an octahydrofused azadecalin structure include those described in U.S. Pat. No. 10,047,082. Exemplary nonsteroidal GRA, SGRA, GRM and SGRM compounds containing a pyrimidine cyclohexyl backbone include compounds disclosed in U.S. Pat. No. 8,685,973. All patents, patent publications and patent applications mentioned herein are incorporated herein by reference in their entirety.

[0059] Exemplary heteroaryl ketone-fused azadecalin compounds are described in U.S. Pat. No. 8,859,774; U.S. Pat. No. 9,273,047; U.S. Pat. No. 9,707,223; and U.S. Pat. No. 9,956,216, all of which are hereby incorporated by reference in their entirety. In an embodiment, the heteroaryl-ketone-fused azadecalin GRA is the compound (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. Pat. No. 8,859,774, also known as "relaquer" and "CORT125134", which has the following structure:

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

[0061] In an embodiment, the heteroaryl ketone-fused azadecalin GRA is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[P,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (also known as "dazucorilant" and "CORT113176"), which has the following structure: Glucocorticoid receptor modulators (GRMs)

[0062] Typically, Cushing's syndrome, Cushing's disease or liver disease can be treated by administering an effective amount of a glucocorticoid receptor modulator (GRM) with any chemical structure or mechanism of action. In an embodiment, the GRM is mifepristone. In an embodiment, the GRM is a selective GRM (SGRM). In an embodiment, liver disease can be treated by administering an effective amount of an SGRM. In a preferred embodiment, Cushing's syndrome, Cushing's disease or liver disease can be treated by administering an effective amount of a non-steroidal SGRM. The categories of exemplary GRMs, particularly exemplary non-steroidal SGRMs, and specific members of the categories are exemplified herein. However, those skilled in the art will easily identify other related or unrelated GRMs and SGRMs that can be used for the methods of treatment described herein.

[0063] In some cases, the nonsteroidal SGRM is relazone (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, which has the following structure:

[0064] Any suitable GRM dosage can be used in the methods disclosed herein. The dosage of the GRM given can be at least about 50 milligrams (mg) / day, or about 100 mg / day, such as 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 an embodiment, GRM is administered orally. In some embodiments, GRM is administered with at least one dose. In other words, GRM can be administered with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In an embodiment, GRM is administered orally with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0065] At least one GRM in one or more doses can be given to a subject within, for example, 2-48 hours. In some embodiments, the GRM is administered in one dose. In other embodiments, the GRM is administered in more than one dose, such as 2, 3, 4, 5 or more doses, during a 2-48 hour period, such as a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 14 hour period, a 16 hour period, a 18 hour period, a 20 hour period, a 22 hour period, a 24 hour period, a 26 hour period, a 28 hour period, a 30 hour period, a 32 hour period, a 34 hour period, a 36 hour period, a 38 hour period, a 40 hour period, a 42 hour period, a 44 hour period, a 46 hour period, or a 48 hour period. In some embodiments, the GRM is administered over a period of 2-48 hours, 2-36 hours, 2-24 hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48 hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36 hours, 24-48 hours, 36-48 hours, or 42-48 hours.

[0066] Single or multiple formulations can be administered according to the dosage and frequency required and tolerated by the patient. The preparation should provide enough active agents to effectively treat the disease state. Therefore, in one embodiment, the daily dose of the pharmaceutical preparation for oral administration of GRM is between about 0.01mg to about 150mg per kilogram of body weight every day (mg / kg / day). In some embodiments, the daily dose is about 1.0-100mg / kg / day, 5-50mg / kg / day, 10-30mg / kg / day and 10-20mg / kg / day. Lower dosages can be used, particularly when the drug is administered to an anatomically hidden position compared to oral administration, such as cerebrospinal fluid (CSF) cavity, enters the blood, enters the body cavity or organ lumen. Obviously higher dosages can be used for local administration.

[0067] The treatment duration of using GRM or SGRM to treat Cushing's syndrome, Cushing's disease or hepatopathy can be changed according to the severity of the object's condition and the reaction of the object to GRM or SGRM. In some embodiments, the administration time course of GRM and SGRM can be about 1 week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks, most typically about 9 weeks to 60 weeks. The suitable time course of administration also includes 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-104 weeks. Suitable time courses for administration also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, 100, and 104 weeks. Typically, administration of a GRM or SGRM should continue until a clinically significant reduction or improvement is observed. Treatment with a GRM or SGRM according to the methods disclosed herein can last for two years or longer.

[0068] In some embodiments, the administration of GRM or SGRM is not continuous, and one or more time courses can be suspended, and then one or more time courses of administration are resumed. The suitable time courses in which administration is suspended include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-100 weeks. Suitable schedules wherein dosing is discontinued also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, and 100 weeks.

[0069] The dosage regimen also takes into account pharmacokinetic parameters well known in the art, i.e., absorption rate, bioavailability, metabolism, clearance rate, etc. (see, 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; the latest Remington, supra). The existing technology allows the clinician to determine the dosage regimen for each patient, GR modulator, and disease or condition being treated.

[0070] SGRMs may be used in combination with other agents known to be useful in modulating the glucocorticoid receptor, or with adjunct agents that may not be effective alone but may aid in the efficacy of the active agent.

[0071] In some embodiments, co-administration includes administering a second activating agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of an activating agent GRM or SGRM. Co-administration includes administering two activating agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or in any order. In some embodiments, co-administration can be completed by co-preparation, i.e., preparing a single pharmaceutical composition comprising two activating agents. In other embodiments, the activating agents can be separately prepared. In another embodiment, the activating agents and / or adjuvants can be connected or coupled to each other.

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

[0073] The pharmaceutical composition can be provided in salt form and 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, etc. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation can be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol in the range of pH 4.5 to 5.5, which is combined with a buffer before use.

[0074] In another embodiment, the composition for treating Cushing's syndrome, Cushing's disease or liver disease can be used for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or organ cavity. The preparation for administration generally includes a solution of the composition dissolved in a pharmaceutically acceptable carrier. Available acceptable carriers and solvents include water and Ringer's solution (isotonic sodium chloride). In addition, sterile non-volatile oils are generally used as solvents or suspension media. To this end, various low-irritation non-volatile oils can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injections. These solutions are sterile and generally do not contain unwanted substances. These preparations can be sterilized by conventional known sterilization techniques. The preparations may contain pharmaceutically acceptable auxiliary substances such as pH regulators and buffers required to simulate physiological conditions, toxicity regulators, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the GRM composition in these preparations can vary greatly and will be selected mainly based on fluid volume, viscosity, body weight, etc., according to the selected specific administration method and the needs of the patient. For intravenous administration, the preparation may be a sterile injectable preparation, such as a sterile injectable aqueous or lipid suspension. The suspension may be prepared using suitable dispersants or wetting agents and suspending agents according to known methods. The sterile injectable preparation may also be a sterile injectable solution or suspension dissolved in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. I. Combination / combination therapy

[0075] Various combinations of GRM or SGRM and another agent (or a combination of such agents and compounds) can be used to treat patient's Cushing's syndrome, Cushing's disease or liver disease.For "combination / joint therapy" or "combination / joint use", it does not mean that therapeutic agents must be given simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein.GRM or SGRM and chemotherapeutic agents can be given according to the same or different dosing regimens.In some embodiments, GRM or SGRM and chemotherapeutic agents are sequentially given in any order throughout the treatment period or part of the treatment period.In some embodiments, GRM or SGRM and anticancer agents are given simultaneously or approximately simultaneously (for example, within about 1, 5, 10, 15, 20 or 30 minutes apart from each other).The non-limiting example of joint therapy is as follows, wherein GRM or SGRM and chemotherapeutic agents are given, for example, GRM or SGRM is "A", and the anticancer 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 the therapeutic compound or agent to the patient will follow the general regimen for administration of such compounds, taking into account the toxicity of the treatment (if necessary). Surgical intervention may also be used in conjunction with the described therapies.

[0080] This approach can be combined with other treatments, such as surgery, radiation therapy, targeted therapy, immunotherapy, or other treatments. Example

[0080] The following examples are provided for illustration only and are not limiting. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially similar results. Example 1. Liver function impairment

[0081] The Phase 1 open-label, multiple-dose study included 18 subjects (18-70 years old), 9 of whom had moderate hepatic impairment (Child-Pugh class B) and 9 were age-, sex-, and weight-matched controls with normal hepatic function.

[0082] Relaqulan was administered at a dose of 300 mg / day for 10 days under fasting conditions. Blood samples for pharmacokinetic (PK) analysis were collected before dosing on Day 1 and before dosing on Day 10 until 144 hours after the last dose of study drug (Day 16). Results: Liver impairment study

[0083] Subjects with moderate hepatic impairment were well matched for age, sex, and weight. The mean total Child-Pugh score for subjects with moderate hepatic impairment was 7.9 (range: 7-9). Liver function was assessed by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Decreases in mean liver function tests (LFTs) were observed in patients with moderate hepatic impairment. Figure 1 Mean changes in LFTs from baseline to Day 16 (144 hours after the last dose of relacyclant) are shown.

[0084] Relazoline Pharmacokinetics (PK): Although the major elimination route of relazoline is the liver, no significant differences were observed between subjects with moderate hepatic impairment and matched controls. Relazoline exposure (measured by area under the curve and maximum plasma concentrations) was largely overlapping in the two groups. Example 2. Study on drug interaction between Rilaconazole and itraconazole

[0085] The Phase 1 open-label fixed-sequence crossover study (NCT03512548) included 25 healthy subjects (18-65 years old). Subjects received relaquintide at a dose of 300 mg once daily for 10 days, followed by relaquintide at a dose of 300 mg once daily and itraconazole at a dose of 200 mg once daily for 10 days. Subjects with AST and / or ALT levels greater than 1.5 times the upper limit of normal (ULN) were excluded from the study.

[0086] A trend toward decreased AST was observed in healthy adults treated with relaconazole in combination with itraconazole (a drug reported to be hepatotoxic). In these subjects, the addition of itraconazole had no relevant effect on the adverse event profile of relaconazole. The mean changes in LFTs in these subjects were as follows: Figure 2 The right column shows the mean change in ALT and AST levels (from baseline to Day 10) for subjects given relaconazole alone; the left column shows the mean change in ALT and AST levels from baseline to Day 11 for subjects given relaconazole in combination with itraconazole. Example 3. Phase 2 Cushing's syndrome study

[0087] The multicenter, open-label study included two dose groups and enrolled 34 patients (age 18-80 years) with endogenous Cushing's syndrome (CS) and impaired glucose tolerance or type 2 diabetes and / or uncontrolled or untreated hypertension. Patients with elevated AST or ALT (elevation defined as greater than 3 times ULN) were excluded.

[0088] The patients were treated with two dose levels of relaquent. The dose in each group was increased by 50 mg every 4 weeks. The low-dose group received relaquent starting at 100 mg / day and gradually increased to 200 mg / day during the 12-week treatment period. The high-dose group received relaquent starting at 250 mg / day and gradually increased to 400 mg / day during the 16-week treatment period.

[0089] Reductions in LFTs were observed in both dose groups, with greater reductions in the high-dose group. ALT normalized in 2 of 4 patients with abnormal ALT values ​​at baseline. Figure 3 As shown, this figure shows the mean change of LFT from baseline to the last observation in the efficacy population (n=34). The leftmost column shows the results of patients in the low-dose group (n=17); the middle column shows the results of patients in the high-dose group (n=17); the rightmost column shows the comprehensive results of all patients (n=34).

[0090] The P values ​​shown are the mean change from baseline to the last observation calculated by the Wilcoxon signed-rank test. The efficacy population included all patients who received relacycline and had post-baseline data. Example 4. Ongoing clinical studies

[0091] Figure 4 A graphic representation of the time course and interventions of four ongoing clinical studies of relaquintide in patients with hypercortisolism is shown. These studies include two Phase 3 studies: 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 withdrawal study of relaquintide in patients with endogenous hypercortisolism of all etiologies. GRADIENT is the first Phase 3, randomized, double-blind, placebo-controlled study of relaquintide in patients with cortisol-secreting adrenal adenomas or adrenal hyperplasia. The Phase 2 / 3 extension study is a study of relaquintide in patients with endogenous hypercortisolism. The Phase 1b study is evaluating relaquintinib in combination with pembrolizumab in patients with metastatic adrenocortical carcinoma and hypercortisolism.

[0092] All patents, patent publications, publications and patent applications cited in this specification are incorporated herein by reference in their entirety, just as if each publication or patent application was specifically and individually incorporated herein by reference. In addition, although described in detail by way of illustration and example for illustrative purposes, it will be readily apparent to those skilled in the art based on the teachings herein that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

Claims

1. A method of treating a patient suffering from a disease selected from the group consisting of liver disease, Cushing's syndrome, Cushing's disease, cancer, fungal infection, bacterial infection, viral infection, inflammatory disease or condition, cardiovascular disease, endocrine disease, kidney disease, and combinations thereof, wherein the method has no adverse effect on the patient's liver, the method comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the disease or a combination thereof, wherein the method has no adverse effect on the patient's liver.

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

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

6. The method of claim 1, wherein: The patient suffers from Cushing's syndrome.

7. The method of claim 1, wherein: The patient suffers from Cushing's disease.

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

9. The method of claim 8, wherein: The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

10. The method of any one of claims 1 to 9, further comprising administering to the patient other pharmaceutical compositions that do not otherwise adversely affect the patient's liver.

11. The method of claim 10, wherein: The other pharmaceutical composition comprises itraconazole or ketoconazole.

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

13. The method of claim 10, wherein: The other pharmaceutical compositions include drugs selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amipheptanate, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methamine, 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, nimetazidine ... Suli, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipran , clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, epoxetine, fealuridine, phepivacetide, fosphenytoin, gemcitabine, levofloxacin, mebanazone, basilamide, niacinamide, nilutamide, nipetidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, torista, fenclorac, bromotidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, meropenem, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, Oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

14. The method of claim 1, wherein: The patient suffers from Cushing's syndrome and liver disease.

15. The method of claim 1, wherein: The patient suffers from Cushing's disease and liver disease.

16. A method of reducing hepatic steatosis in a patient suffering from a disease selected from the group consisting of liver disease, Cushing's syndrome, Cushing's disease, cancer, fungal infection, bacterial infection, viral infection, inflammatory disease or disorder, cardiovascular disease, endocrine disease, and renal disease, and combinations thereof, The method comprises administering to a patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the disease or a combination thereof, the method having no adverse effect on the patient's liver and being effective in reducing hepatic steatosis in the patient.

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

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

21. The method of claim 16, wherein: The patient suffers from Cushing's syndrome.

22. The method of claim 16, wherein: The patient suffers from Cushing's disease.

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

24. The method of claim 23, wherein: The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

25. The method of any one of claims 16 to 24, further comprising administering to the patient other pharmaceutical compositions that do not otherwise adversely affect the patient's liver.

26. The method of claim 25, wherein: The other pharmaceutical composition comprises itraconazole or ketoconazole.

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

28. The method of claim 25, wherein: The other pharmaceutical compositions include drugs selected from the group consisting of mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amipheptanate, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methamine, 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, nimetazidine ... Suli, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipran , clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, epoxetine, fealuridine, phepivacetide, fosphenytoin, gemcitabine, levofloxacin, mebanazone, basilamide, niacinamide, nilutamide, nipetidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, torista, fenclorac, bromotidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, meropenem, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, Oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

29. The method of claim 16, wherein: The patient suffers from Cushing's syndrome and liver disease.

30. The method of claim 16, wherein: The patient suffers from Cushing's disease and liver disease.

31. A method of reducing or preventing hepatotoxicity in a patient receiving a drug that may cause hepatotoxicity, the method comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) in addition to the drug that may cause hepatotoxicity.

32. The method of claim 31, wherein: The patient was receiving the potentially hepatotoxic drug and then the SGRM was administered to him.

33. The method of claim 31, wherein: The patient was receiving the SGRM and then given the drug that could cause hepatotoxicity.

34. The method of claim 31, wherein: The patient suffers from fatty liver disease.

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

38. The method of claim 31, wherein: The patient suffers from Cushing's syndrome.

39. The method of claim 31, wherein: The patient suffers from Cushing's disease.

40. The method of 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. The method of claim 40, wherein: The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

42. The method of any one of claims 31 to 41, wherein: Drugs that may cause hepatotoxicity are CYP3A inhibitors selected from the following: ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranavir, paritaprevir, and voriconazole.

43. The method of any one of claims 31 to 41, wherein: Drugs that may cause hepatotoxicity are selected from the following: mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amitriptyline, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, nimetazodine Suli, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipran , clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, epoxetine, fealuridine, phepivacetide, fosphenytoin, gemcitabine, levofloxacin, mebanazone, basilamide, niacinamide, nilutamide, nipetidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, torista, fenclorac, bromotidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, meropenem, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, Oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

44. The method of any one of claims 31 to 41, wherein: A drug that may cause hepatotoxicity is ketoconazole.

45. The method of any one of claims 31-41, wherein the drug that may cause hepatotoxicity is itraconazole.

46. ​​The method of any one of claims 31 to 45, wherein: The patient suffers from Cushing's syndrome and liver disease.

47. The method of any one of claims 31 to 46, wherein: The patient suffers from Cushing's disease and liver disease.

48. A method of treating a patient receiving a drug that may cause hepatotoxicity without adversely affecting the patient's liver, the method comprising administering to the patient an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to treat the patient who is receiving the drug that may cause hepatotoxicity without adversely affecting the patient's liver.

49. The method of claim 48, wherein: The patient was receiving the potentially hepatotoxic drug and then the SGRM was administered to him.

50. The method of claim 48, wherein: The patient was receiving the SGRM and then given the drug that could cause hepatotoxicity.

51. The method of claim 48, wherein: The patient suffers from fatty liver disease.

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. 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. The method of claim 53, wherein: The non-alcoholic fatty liver disease (NAFLD) is non-alcoholic steatohepatitis (NASH) or non-alcoholic cirrhosis.

55. The method of claim 48, wherein: The patient suffers from Cushing's syndrome.

56. The method of claim 48, wherein: The patient suffers 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. The method of claim 57, wherein: The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

59. The method of any one of claims 48 to 58, wherein: Drugs that may cause hepatotoxicity are CYP3A inhibitors selected from the following: ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranavir, paritaprevir, and voriconazole.

60. The method of any one of claims 48 to 58, wherein: Drugs that may cause hepatotoxicity are selected from the following: mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amitriptyline, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, nimetazodine Suli, minocycline, alatrofloxacin mesylate, gemtuzumab ozogamicin, acetazolamide, benoxaprofen, bromfenac, danazol, febuxostat, griseofulvin, ibufenac, sunitinib, methimazole, sulfathiazole, terbinafine, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipran , clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, epoxetine, fealuridine, phepivacetide, fosphenytoin, gemcitabine, levofloxacin, mebanazone, basilamide, niacinamide, nilutamide, nipetidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, torista, fenclorac, bromotidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, meropenem, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, Oxymetholone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

61. The method of any one of claims 48 to 58, wherein: A drug that may cause hepatotoxicity is ketoconazole.

62. The method of any one of claims 48-58, wherein the drug that may cause hepatotoxicity is itraconazole.

63. The method of any one of claims 48 to 62, wherein: The patient suffers from Cushing's syndrome and liver disease.

64. The method of any one of claims 48 to 63, wherein: The patient suffers from Cushing's disease and liver disease.

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

66. The method of claim 65, wherein: The nonsteroidal SGRM is relaquinone (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, which has the following formula:

67. The method of any one of claims 48 to 66, wherein The patient suffers from elevated liver enzyme levels of alanine aminotransferase in the blood, wherein administration of the non-steroidal SGRM compound does not increase the liver enzyme levels in the blood.

68. The method of any one of claims 48 to 67, wherein The patient suffers from elevated liver enzyme levels of the liver enzyme aspartate aminotransferase in the blood, wherein administration of the non-steroidal SGRM compound does not increase the liver enzyme levels in the blood.

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

70. The method of any one of claims 48 to 68, wherein: The patient has received a drug selected from the following: mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amifampic acid, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipranvir, Clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, cyclopentolone, fealuridine, phenytoin, gemcitabine, levofloxacin, mebanazone, pyrimidine, niacinamide, nilutamide, niperidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, toristastat, fenclorac, bromitidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, maceprazine, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, hydroxy Methedrolone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, 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 had received ketoconazole.

72. The method of any one of claims 48 to 68, wherein: The patient had received itraconazole.

73. Use of a non-steroidal selective glucocorticoid receptor modulator in the treatment of a disease selected from Cushing's syndrome, Cushing's disease and fatty liver disease without adverse effects on liver enzyme levels or liver function, wherein: The use is combined with drugs that may cause liver toxicity.

74. The use according to claim 73, wherein The disease is Cushing's syndrome.

75. The use according to claim 73, wherein The disease is Cushing's disease.

76. The use according to claim 73, wherein The disease is fatty liver disease.

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

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

79. The use according to 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. The use of claim 80, wherein The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

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

83. The use according to any one of claims 73 to 81,It includes the combined use of drugs selected from the following: mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amitriptyline, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipranvir, Clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, cyclopentolone, fealuridine, phenytoin, gemcitabine, levofloxacin, mebanazone, pyrimidine, niacinamide, nilutamide, niperidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, toristastat, fenclorac, bromitidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, maceprazine, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, hydroxy Methedrolone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

84. The use of any one of claims 73-81, comprising the combined use of ketoconazole.

85. The use according to any one of claims 73 to 81, comprising the combined use of itraconazole.

86. Use of a non-steroidal selective glucocorticoid receptor modulator in the preparation of a medicament for treating a disease selected from Cushing's syndrome, Cushing's disease and fatty liver disease and having no adverse effects on liver enzyme levels or liver function, wherein: The use is combined with drugs that may cause liver toxicity.

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

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

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

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

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. 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. The use of claim 93, wherein The non-steroidal selective glucocorticoid receptor modulator is relaquinone (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, which has the following formula:

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

96. The use according to any one of claims 87 to 94,It includes the combined use of drugs selected from the following: mercaptopurine, indomethacin, phenytoin, rifampicin, abacavir, allopurinol, amitriptyline, amiodarone, bicalutamide, chlorzoxazone, actinomycin D, dantrolene, diclofenac, diflunisal, fenoprofen, flutamide, hydroxyurea, imatinib, iproniazid, ketoconazole, labetalol, leflunomide, phenacyl methionine, 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, tinidic acid, trovafloxacin, etravirine, tolvaptan, pazopanib, divalproex sodium, lumiracoxib, tasosartan, oxitinib, bromoquinol, alclofenac, apravirol, clomaclen, dermatan, isathonin, pipamazine, precasan, sulfonylurea, triacetin, fedocetin, pavudine, phenoxyprohydrazine, oxandrolone, acarbose, apidem, bexarotene, voriconazole, benzadone, benzalone, beniodarone, atomoxetine, clomezazone, erlotinib, cincofen, tipranvir, Clomethacin, sorafenib, darunavir, cyclofenil, didanosine, interferon α-2b, interferon α-2a, recombinant, droxicam, ethambutol, infliximab, cyclopentolone, fealuridine, phenytoin, gemcitabine, levofloxacin, mebanazone, pyrimidine, niacinamide, nilutamide, niperidine, nomifensine, nortriptyline, pirprofen, riluzole, ritonavir, sucrose, toristastat, fenclorac, bromitidine, nitrazol, tetracarbamate, benzylbenzamide, zafirlukast, flunidamol, zimelidine, telithromycin, ximelagatran, duloxetine, glafenine, maceprazine, apatinib, alapropamide, orlistat, sitaxentan, carbamipine, felbamate, ciprofloxacin, hydroxy Methedrolone, niacin, cyclosporine, albendazole, deferasirox, thiabendazole, raltegravir, dronedarone, bosentan, micafungin, bortezomib, milnacipran, asparaginase, efavirenz, interferon beta-1b, interferon beta-1a, interferon alpha combination, lamotrigine, nandrolone decanoate, dacarbazine, acetaminophen, azathioprine, erythromycin, sulfasalazine, isotretinoin, atorvastatin, clozapine, 4-aminosalicylic acid, zileuton, acitretin, natalizumab, papaverine, dimethoate, ticlopidine, exemestane, gefitinib, eltrombopag, oxaliplatin, diltiazem, estramustine, peginterferon alfa-2b, methotrexate, cytarabine, maraviroc, mexiletine, and pentostatin.

97. The use of any one of claims 87-94, comprising the combined use of ketoconazole.

98. The use according to any one of claims 87 to 94, comprising the combined use of itraconazole.

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