Concomitant administration of selective glucocorticoid receptor modulator relacorilant and p-glycoprotein substrates

Abstract

Relacorilant is a selective modulator of the type II glucocorticoid receptor (GR); it may be orally administered. Applicant discloses in vitro studies that show relacorilant to be a potent inhibitor of P-glycoprotein (P-gp). Surprisingly, in vivo studies of co-administration of relacorilant and dabigatran etexilate (a P-gp substrate) showed that relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures, suggesting that only minimal or no dose adjustments are needed for P-gp substrates upon coadministration with relacorilant. The surprising finding that relacorilant may be safely co-administered with P-gp substrates without need for significant dose adjustment provides improved methods and uses for treatment of such disorders as, for example, hypercortisolism (e.g., Cushing's syndrome, Cushing's Disease), hyperglycemia, hypertension, and a solid tumor in combination with chemotherapy or immunotherapy agents.

Description

PATENT Attorney Docket No.085178-1509851-018710WO Concomitant Administration of Selective Glucocorticoid Receptor Modulator Relacorilant and P-Glycoprotein Substrates BACKGROUND

[0001] Although many pharmacologic agents have excellent efficacy and may lead to only a few or minor side-effects, some pharmacologic agents may interact with other such agents. Such interactions may lead to altered efficacy of a pharmacologic agent administered to a patient while that patient is also taking (or eating) such other agents. Thus, it may be important to identify possible drug-drug interactions in order to mitigate or avoid them.

[0002] P-glycoprotein (P-gp), also known as multi-drug resistance protein 1 (MDR1), is an adenosine triphosphate (ATP)-dependent efflux pump with broad substrate specificity that acts as a pump to transport molecules across the cell membrane and out of cells. In humans, it is encoded by the ABCB1 gene. P-gp has a significant impact on the gastrointestinal absorption and systemic disposition of its substrates. Its activity is important for cellular homeostasis, and, by pumping compounds out of cells, plays an important role in reducing intracellular levels of some drugs administered to patients, thereby affecting the ability of those drugs to perform their clinical actions. Many drugs are substrates for P-gp; thus, inhibiting P-gp will cause higher intra cellular concentrations of such drugs. P-gp is found in intestine, liver, and kidney, and can play an important role in removing administered drugs from circulation and shunting those drugs out of the body.

[0003] Many drugs affect P-gp activity; some drugs that are substrates for P-gp activity (e.g., dabigatran etexilate, digoxin, edoxaban, fexofenadine, clarithromycin, cyclosporin, colchicine, diltiazem, erythromycin, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine) are pumped out of cells and their intracellular concentrations may be increased when administered with compounds (e.g., cyclosporine, carvedilol, clarithromycin, amiodarone, dronedarone, itraconazole, ketoconazole, lapatinib, quinidine, reserpine, ritonavir, tacrolimus, tariquidar, elacridar, verapamil, and valspodar (PSC833) that inhibit P-gp activity. Other drugs may increase P-gp activity; for example, P-gpinducers such as, e.g., carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazosin, rifampicin (rifampin), St. John’s wort, tenofovir, tipranovir, trazodone, and vinblastine, may increase P-gp activity. Thus co-administration of a first and a second drug must take into account not only how the levels of a first drug are affected by P-gp, but also how the second drug affects P-gp and so may affect the levels of the first drug; and vice versa.

[0004] P-glycoprotein affects the plasma levels of direct oral anticoagulants (DOACs) that are substrates for P-gp — such as dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa), and betrixaban (Bevyxxa) – which are anticoagulants used for the prevention of thrombosis in several cardiovascular contexts. For example, dabigatran (administered as dabigatran etexilate) is an anticoagulant prescribed for the prevention and treatment of blood clots – which may lead to deep vein thrombosis (DVT), pulmonary embolism (PE), venous thromboembolism (VTE), strokes, and other adverse disorders. Patients suffering from atrial fibrillation, or patients who have had hip replacement surgery, or others at risk of blood clots, may be prescribed dabigatran. Patients with high levels of cortisol (e.g., patients suffering from hypercortisolemia, e.g., those suffering from Cushing’s syndrome) may be at greater than normal risk of blood clots. Published data regarding human exposure to administered dabigatran are discussed in, for example, Stangier et al., J Clin Pharmacol.2005 May;45(5):555-563; Hartter et al., Br J Clin Pharmacol. 201274(3): 490-500; and Hartter et al., Br J Clin Pharmacol.201275(4): 1053-1062.

[0005] Relacorilant (CORT125134) is an orally administered selective glucocorticoid receptor modulator without affinity for the progesterone receptor. Cortisol, an endogenous hormone that binds to the glucocorticoid receptor (GR), plays important roles in affecting metabolism, the cardiovascular system, the immune system, and many other systems and bodily functions and responses. Relacorilant is in development for the treatment of endogenous Cushing syndrome (hypercortisolism), hyperglycemia and hypertension related to hypercortisolemia, and for treatment of solid tumors in combination with chemotherapy or immunotherapy agents.

[0006] The pharmacokinetics of many drugs are affected by P-gp. Where a patient is administered two or more drugs, oral absorption and systemic disposition of one of the administered drugs that is a substrate for P-gp is affected by the other administered drug that is either a P-gp inhibitor or P-gp inducer. Enhanced P-gp activity resulting from an inductiontypically increases elimination of drugs which are substrates of P-gp, so that inducing greater P- gp activity reduces systemic levels of P-gp substrate drugs as compared to the levels that would be obtained in a patient without increased P-gp activity. Thus, strong inducers of P-gp activity act to reduce the levels of other, P-gp substrate drugs administered or present along with such P- gp inducers.

[0007] Strong inhibitors of P-gp administered or present in the system of a patient, while that patient is administered a drug that is a P-gp substrate, are expected to reduce elimination of P-gp substrate drugs as compared to their elimination in the absence of the P-gp inhibitor. Thus, if the dosage of a P-gp substrate drug is not adjusted when administered along with a P-gp inhibitor, the plasma concentration levels of P-gp substrate drugs would be increased as compared to their plasma concentration levels obtained in the patient from that dose of P-gp substrate drug in the absence of P-gp inhibitors. Such increased plasma concentration levels could lead to overdoses of the P-gp substrate drug. Thus, knowledge of whether and how a drug interacts with P-gp is clinically important, since its administration with other drugs may affect P-gp activity, or be affected by P-gp activity, and so alter the plasma concentration levels and clinical effects of those other drugs, or its plasma concentration levels and clinical effects may be altered by those other drugs. Accordingly, it is important to identify and measure the effects of a drug on P-gp and on other drugs co-administered with that drug. SUMMARY

[0008] Relacorilant is disclosed to be a potent in vitro inhibitor of P-gp, with an IC50of 1.3 μM. Thus, relacorilant would be expected to have significant effects on levels of P-gp substrate drugs when co-administered to subjects (or present at the same time in the subject’s body) with relacorilant.

[0009] Surprisingly, in vivo studies demonstrate little to no effect of relacorilant co- administration on levels of the P-gp substrate dabigatran etexilate as compared to dabigatran etexilate levels in the absence of relacorilant.

[0010] Methods of treatment, and uses, of relacorilant are disclosed herein in which relacorilant may be safely co-administered with P-gp substrate drugs without significant adjustment of the P- gp substrate drug dosages as compared to such dosages administered in the absence of relacorilant.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG.1 presents a table providing comparisons of exposures following oral administration of dabigatran etexilate. Subjects received a 75 milligram (mg) single dose of dabigatran etexilate on the day before and on the day after receiving, for each of 11 days, administration of 400 mg once-daily (QD) doses of relacorilant. The table presents the geometric mean ratios and 90% confidence interval (CI) for Cmax and AUC0-inf for free dabigatran and for total dabigatran (where the ratios are the respective dabigatran levels in the presence of relacorilant divided by the respective dabigatran levels in the absence of relacorilant).

[0012] FIG.2 presents a Log10 / Linear graph illustrating plasma free dabigatran concentrations following the administration of single oral doses of 75 mg dabigatran etexilate either alone (on Day 1) or in the presence of relacorilant (Day 12). 400 mg doses of relacorilant were given once daily for each of 11 days prior to the measurements made on Day 12. Data points are geometric mean values, error bars are ± geometric Standard Deviation.

[0013] FIG.3 presents a Log10 / Linear graph illustrating plasma total dabigatran concentrations following the administration of single oral doses of 75 mg dabigatran etexilate either alone (on Day 1) or in the presence of relacorilant (Day 12). 400 mg doses of relacorilant were given once daily for each of 11 days prior to the measurements made on Day 12. Data points are geometric mean values, error bars are ± geometric Standard Deviation. DETAILED DESCRIPTION

[0014] Relacorilant was found to be a potent inhibitor of P-gp transport of the test compound digoxin in in vitro studies with an IC50value of 1.3 μM. Such inhibition would be expected to lead to similar inhibition of P-gp transport in vivo, and thus, in order to maintain safe drug levels in the patient, would be expected to require dose adjustment of relacorilant or of P-gp substrates, or both, when relacorilant and a P-gp substrate are co-administered to a patient.

[0015] Applicant discloses herein the surprising finding that in vivo studies of concomitant administration of relacorilant and dabigatran etexilate (a P-gp substrate) showed that relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures. There were only small numeric increases in free and total dabigatran plasma Cmax in the presence of relacorilant compared to dabigatran alone; these increases were not considered to be clinicallyrelevant. Overall, 400 mg once-daily administration of relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures. These results suggest that no dose adjustments are needed for P-gp substrates administered concomitantly with relacorilant, and that relacorilant may be safely administered to patients also receiving drugs which are P-gp substrates without significant dose adjustment of the relacorilant dose or of the dose of the drugs which are P-gp substrates. Thus, surprisingly, concomitant administration of relacorilant and a P-gp substrate drug is safe and may be performed with no drug dose adjustment of a P-gp substrate as compared to dosages used in the absence of relacorilant.

[0016] Relacorilant may be orally administered.

[0017] Relacorilant may be administered at any suitable dose. Relacorilant may be administered once per day in amounts between about 10 milligrams (mg) to about 1000 mg, or between about 25 mg to about 600 mg. In embodiments, the effective amount of relacorilant is a daily dose of between 0.1 and 10 mg / kg / day.

[0018] For example, safe and effective doses of relacorilant include daily doses, and include oral doses, of relacorilant between about 10 milligrams (mg) and about 500 mg. Such safe and effective doses may be, for example, 10 mg, 25 mg, 50 mg, 75, mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg. Relacorilant may be administered with food. In embodiments, relacorilant may be administered without food, and may be administered to a fasted patient without food. (A fasted patient is one who has not eaten within an hour prior to, and after, drug administration.)

[0019] The surprising finding that relacorilant may be administered with P-gp substrates such as, e.g., dabigatran etexilate, provides improved methods of treatment for disorders amenable to treatment by relacorilant. Such disorders amendable to treatment with relacorilant include, for example, hypercortisolism (e.g., Cushing’s syndrome and Cushing’s Disease), hyperglycemia, hypertension, solid tumors in combination with chemotherapy or immunotherapy agents, and other disorders. The present methods provide improved methods of treating these and other disorders without need for adjustment of relacorilant dose when relacorilant is administered concomitantly with a P-gp substrate.INTRODUCTION

[0020] Relacorilant is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2- yl)methanone (also known as “CORT125134”), which has the following structure:(Example 18 of U.S. Patent 8,859,774, which patent is hereby incorporated by reference in its entirety).

[0021] Relacorilant was found to inhibit P-gp transport of the test compound digoxin in in vitro studies (with an IC50 of 1.3 μM). Such inhibition would be expected to lead to significant inhibition of P-gp transport in vivo, and thus to require dose adjustment of relacorilant or of P-gp substrates, or both, when relacorilant and a P-gp substrate are concomitantly administered to a patient. Applicant discloses herein the surprising finding that in vivo studies of concomitant administration of relacorilant and dabigatran etexilate (a P-gp substrate) showed that relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures, suggesting that no dose adjustments are needed for P-gp substrates upon concomitant administration with relacorilant. These studies support the conclusion that relacorilant may be safely administered to patients also receiving drugs which are P-gp substrates without significant dose adjustment of the relacorilant dose or of the dose of the P-gp substrate drug.

[0022] Relacorilant is being studied in clinical trials for Cushing’s syndrome and solid tumors in combination with chemotherapy or immunotherapy agents, and is believed to be useful in the treatment of many disorders. For example, relacorilant is a selective modulator of the glucocorticoid receptor (GR), and is believed to be useful in the treatment of disorders of cortisol dysregulation, including cortisol excess, such as hypercortisolism (e.g., Cushing’s syndrome and Cushing’s Disease), hyperglycemia, hypertension, solid tumors in combination with chemotherapy or immunotherapy agents, and other disorders. For example, relacorilant in combination with taxane chemotherapy is useful in the treatment of ovarian and other cancers offemale reproductive tissues (see U.S. Patent 12,109,272; see also, for example, U.S. Patents 11,684,612; 11,590,113; 11,058,670; 11,524,013; and 9,956,216, all of which patents are hereby incorporated by reference in their entireties).

[0023] Accordingly, in embodiments, Applicants disclose methods of treating a patient suffering from a disorder amenable to treatment by relacorilant, the method comprising administering to said patient an effective amount of relacorilant, concomitantly with administration of an effective amount of a drug which is a P-glycoprotein (P-gp) substrate, and, wherein said effective amount of said drug which is a P-gp substrate is the same as the effective amount of said P-gp substrate drug when said P-gp substrate drug is administered in the absence of relacorilant, effective to treat said disorder amenable to treatment by relacorilant.

[0024] Accordingly, in embodiments, Applicants disclose uses of relacorilant, and pharmaceutical formulations containing relacorilant as an active ingredient, for treating a patient suffering from a disorder amenable to treatment by relacorilant, wherein said treatment comprises administering an effective amount of a relacorilant to a patient suffering from said disorder amenable to treatment by relacorilant, wherein said patient is concomitantly administered an effective amount of a drug which is a P-glycoprotein (P-gp) substrate, wherein said effective amount of said P-gp substrate drug is the same as the effective amount of said P-gp substrate drug when said drug is administered in the absence of relacorilant.

[0025] A disorder amenable to treatment by relacorilant may be, for example, hypercortisolism (e.g., Cushing’s syndrome and Cushing’s Disease), hyperglycemia, hypertension, solid tumors in combination with chemotherapy or immunotherapy agents, and other disorders.

[0026] Examples of P-gp substrate drugs include, e.g., dabigatran etexilate, digoxin, edoxaban, fexofenadine, clarithromycin, cyclosporin, colchicine, diltiazem, erythromycin, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine.

[0027] As discussed above, in embodiments of these methods and uses, the effective amount of relacorilant may be, for example, an amount selected from 10 mg, 25 mg, 50 mg, 75, mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg. In embodiments of these methods and uses, administration of relacorilant is oral administration. In embodiments of these methods and uses,administration of relacorilant is daily administration. In embodiments of these methods and uses, administration of relacorilant is once daily administration. In embodiments of these methods and uses, relacorilant administration is administration with food. In embodiments of these methods and uses, relacorilant administration is administration without food. DEFINITIONS

[0028] As used herein, the term “about”, e.g., as used in the phrase “about X” where X is a numerical value, is used to indicate a range of ±10% of the named value of X.

[0029] As used herein, the terms “same”, “same as”, “the same as”, and the like, e.g., as used in the phrase “X is the same as Y” where Y is a numerical value or amount having a numerical value, is used to indicate that X is equivalent to a value or amount within ±10% of Y.

[0030] As used herein, the term “substantially”, e.g., as used in the phrase “X is substantially the same as Y” refers to a value of X that is within about 30%, or within about 25%, or within about 20%, or within about 15%, or within about 10% of the value of the term Y.

[0031] As used herein, the abbreviation “P-gp” refers to P-glycoprotein, which is also known as multi-drug resistance protein 1 (MDR1). In humans, it is encoded by the ABCB1 gene. Human P-gp is encoded by more than one isoform, including, for example, the 1350 amino acid ATP- dependent translocase ABCB1 isoform 1 [Homo sapiens] (NCBI Reference Sequence: NP_001335874.1), and the 1280 amino acid ATP-dependent translocase ABCB1 isoform 2 [Homo sapiens] (NCBI Reference Sequence: NP_001335875.1) isoforms. P-gp is an ATP-driven pump protein which transports molecules across the cell membrane and out of cells. P-gp is found in intestine, liver, and kidney, among other organs, and can play an important role in removing administered drugs from circulation and shunting those drugs out of the body.

[0032] As used herein, phrases such as, e.g., “P-gp substrate”, “substrate of P-gp”, and the like refer to compounds which may be acted upon by P-gp and transported out of a cell expressing P- gp. Listings of P-gp substrates may be found, for example, on the web-site “go.drugbank.com” at the page “categories / DBCAT002668” and on the web-site “www.fda.gov” at the page “drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers#table4-1”. P-gp substrates include, for example, Abemaciclib, Acebutolol, Acenocoumarol, Acetaminophen, Acetylsalicylic acid, Afatinib, Albendazole,Aldosterone, Alectinib, Alfuzosin, Aliskiren, Alitretinoin, alpha-Tocopherol acetate, Ambrisentan, Amisulpride, Amitriptyline, Amlodipine, Amprenavir, Anastrozole, Apixaban, Apremilast, Aprocitentan, Artesunate, Asciminib, Asunaprevir, Atazanavir, Atogepant, Atorvastatin, Avacopan, Avanafil, Avatrombopag, Axitinib, Azathioprine, Azithromycin, Baloxavir marboxil, Baricitinib, Beclomethasone dipropionate, Belantamab mafodotin, Belinostat, Belumosudil, Belzutifan, Berotralstat, Betamethasone, Betamethasone phosphate, Betrixaban, Bexagliflozin, Binimetinib, Bisoprolol, Bortezomib, Bosutinib, Bromocriptine, Budesonide, Cabazitaxel, Cabergoline, Cabotegravir, Camptothecin, Canagliflozin, Capmatinib, Carbamazepine, Carfilzomib, Celecoxib, Ceritinib, Cerivastatin, Cethromycin, Cetirizine, Chloramphenicol succinate, Chloroquine, Chlorpromazine, Cimetidine, Ciprofloxacin, Citalopram, Cladribine, Clarithromycin, Clindamycin, Clobazam, Clofazimine, Clomifene, Clopidogrel, Clotrimazole, Clozapine, Cobimetinib, Colchicine, Conjugated estrogens, Copanlisib, Cortisone acetate, Crizotinib, Curcumin, Cyclosporine, Dabigatran etexilate, Dabrafenib, Daclatasvir, Dacomitinib, Dactinomycin, Dapagliflozin, Daptomycin, Darolutamide, Darunavir, Dasabuvir, Dasatinib, Daunorubicin, Debrisoquine, Deucravacitinib, Dexamethasone, Dexamethasone acetate, Diazepam, Diethylstilbestrol, Digitoxin, Digoxin, Diltiazem, Dipyridamole, Docetaxel, Dolutegravir, Domperidone, Doxepin, Doxorubicin, Duvelisib, Edoxaban, Elagolix, Elbasvir, Eletriptan, Elexacaftor, Eliglustat, Empagliflozin, Enasidenib, Encorafenib, Enfortumab vedotin, Entrectinib, Epinastine, Erdafitinib, Erlotinib, Ertugliflozin, Erythromycin, Escitalopram, Esomeprazole, Estradiol, Estradiol acetate, Estradiol benzoate, Estradiol cypionate, Estradiol dienanthate, Estradiol valerate, Estriol, Estrone, Ethinylestradiol, Etoposide, Everolimus, Ezetimibe, Fedratinib, Fesoterodine, Fexofenadine, Fidaxomicin, Filgotinib, Flecainide, Fluticasone, Fluticasone furoate, Fluticasone propionate, Fostemsavir, Futibatinib, Gefapixant, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Glecaprevir, Gramicidin D, Grapiprant, Grazoprevir, Grepafloxacin, Haloperidol, Hydrocortisone, Hydroxyzine, Ibrexafungerp, Ibuprofen, Idelalisib, Imatinib, Imipramine, Indacaterol, Indinavir, Indomethacin, Infigratinib, Inotuzumab ozogamicin, Irinotecan, Ivermectin, Ivosidenib, Ixabepilone, Ketazolam, Ketoconazole, Lamivudine, Lamotrigine, Lansoprazole, Larotrectinib, Lasmiditan, Ledipasvir, Lefamulin, Lemborexant, Lenacapavir, Lenalidomide, Leniolisib, Lenvatinib, Letermovir, Letrozole, Levamlodipine, Levetiracetam, Levofloxacin, Levomilnacipran, Linagliptin, Lonafarnib, Lonapegsomatropin, Loncastuximab tesirine, Loperamide, Loratadine,Losartan, Lurbinectedin, Lusutrombopag, Mannitol, Mavorixafor, Medrysone, Mefloquine, Meperidine, Methotrexate, Methylene blue, Methylprednisolone, Metoclopramide, Mibefradil, Midazolam, Mirabegron, Mirvetuximab soravtansine, Mitapivat, Mitoxantrone, Mobocertinib, Momelotinib, Monensin, Morphine, Mycophenolate mofetil, Nadolol, Naloxone, Nelfinavir, Nicardipine, Nifedipine, Nilotinib, Nintedanib, Niraparib, Nirmatrelvir, Nirogacestat, Nitrofurantoin, Nizatidine, Nortriptyline, Octreotide, Odanacatib, Odevixibat, Olanzapine, Olaparib, Olopatadine, Omadacycline, Ombitasvir, Omeprazole, Opicapone, Osimertinib, Oxcarbazepine, Ozanimod, Paclitaxel, Palbociclib, Paliperidone, Panobinostat, Pantoprazole, Paritaprevir, Pazopanib, Pemigatinib, Pentazocine, Phenobarbital, Phenytoin, Pibrentasvir, Pirtobrutinib, Pitavastatin, Platelet Activating Factor, Polatuzumab vedotin, Pomalidomide, Ponatinib, Posaconazole, Pralsetinib, Pravastatin, Prazosin, Prednisolone, Prednisolone acetate, Prednisolone phosphate, Prednisone, Progesterone, Propranolol, Prucalopride, Quetiapine, Quinidine, Quinine, Quizartinib, Raloxifene, Ranitidine, Ranolazine, Regorafenib, Relugolix, Remdesivir, Repotrectinib, Reserpine, Revefenacin, Rhodamine 6G, Rifamycin, Rimegepant, Riociguat, Ripretinib, Risdiplam, Risperidone, Ritonavir, Rivaroxaban, Romidepsin, Rucaparib, Saquinavir, SAR-405838, Selexipag, Selpercatinib, Selumetinib, Sildenafil, Silodosin, Simeprevir, Simvastatin, Sirolimus, Sitagliptin, Sofosbuvir, Somatostatin, Somatotropin, Sorafenib, Sparfloxacin, Sparsentan, Sphingosine, Stanolone, Stanolone acetate, Sulpiride, Sumatriptan, Sunitinib, Tacrine, Tacrolimus, Talazoparib, Talinolol, Tamoxifen, Taurocholic acid, Tazemetostat, Technetium Tc-99m sestamibi, Tegaserod, Telaprevir, Telotristat ethyl, Temozolomide, Temsirolimus, Tenofovir, Tenofovir alafenamide, Tenofovir disoproxil, Tepotinib, Terfenadine, Testosterone propionate, Tezacaftor, Ticagrelor, Timolol, Tipranavir, Tisotumab vedotin, Tivozanib, Tolvaptan, Topiramate, Topotecan, Toremifene, Trastuzumab deruxtecan, Trastuzumab emtansine, Trifluoperazine, Trilaciclib, Trimethoprim, Trimipramine, Tucatinib, Ubidecarenone, Ubrogepant, Umeclidinium, Upadacitinib, Valinomycin, Valspodar, Vardenafil, Vecuronium, Velpatasvir, Vemurafenib, Venetoclax, Venlafaxine, Verapamil, Vericiguat, Vibegron, Vilanterol, Vildagliptin, Vinblastine, Vincristine, Vinflunine, Vismodegib, Voclosporin, Voxilaprevir, Zanubrutinib, Zavegepant, and Zidovudine.

[0033] As used herein, the term “patient” refers to a human that is or will be receiving, or has received, medical care for a disease or condition. The term “subject” may also refer to a patient.

[0034] As used herein, the term “disorder amenable to treatment by relacorilant” refers to any disorder or disease for which administration of relacorilant may provide clinical benefit. For example, relacorilant is believed to be useful in the treatment of useful in the treatment of disorders of cortisol dysregulation, including cortisol excess. Disorders amenable to treatment by relacorilant include, without limitation, hypercortisolism (e.g., Cushing’s syndrome and Cushing’s Disease), hyperglycemia, hypertension, solid tumors in combination with chemotherapy or immunotherapy agents, and other disorders.

[0035] As used herein, the terms "treat", "treating", "treatment", and the like refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, laboratory analysis of a sample obtained from a subject, neuropsychiatric examinations, and / or a psychiatric evaluations.

[0036] As used herein, the term “effective amount” or “therapeutic amount” refers to an amount of a pharmacological agent effective to treat, eliminate, or mitigate at least one symptom of the disease being treated. In some cases, “therapeutically effective amount” or “effective amount” can refer to an amount of a functional agent or of a pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount can be an amount effective to invoke an antitumor response. For the purpose of this disclosure, the effective amount of relacorilant is an amount that would bring about the desired beneficial clinical outcomes.

[0037] As used herein, the terms “administer,” “administering,” “administered” or “administration” refer to providing a compound or a composition (e.g., one described herein), to a subject or patient. For example, a compound or composition may be administered orally to a patient.

[0038] As used herein, the terms “co-administration”, “concomitant administration”, “concomitantly administer”, and the like, refer to the administration to a patient of a first drug inthe presence of a second drug. The presence of the second drug may be due to administration of the second drug at the same time as the first drug is administered; or may be due to administration of the second drug before administration of the first drug; or may be due to administration of the second drug after administration of the first drug. In all cases, both the first and the second drug are present in the body of the patient at the same time.

[0039] As used herein, the terms “co-administrative amount” and “concomitant amount” refer to the amount of a first drug that is safe and effective when that drug is administered along with a second drug. For example, where a second drug affects the plasma level of a first drug, the co- administrative amount of the amount of the first drug adjusted so that the plasma level of the first drug, when co-administered with the second drug, provides a safe and effective amount of the first drug in the patient.

[0040] As used herein, the term “combination therapy” refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously, or sequentially in any order during the entire or portions of the treatment period. The at least two agents may be administered following the same or different dosing regimens. In some cases, one agent is administered following a scheduled regimen while the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, the one pharmaceutical agent, e.g., relacorilant, is administered daily, and the other pharmaceutical agent, may be administered every two, three, or four days, or at other intervals.

[0041] As used herein, the term "compound" is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety ("compound") may exist in a free species form, in which it is not associated with other molecules. A compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity.

[0042] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound,use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0043] The term “measuring the level” refers determining, detecting, or quantitating the amount, level, or concentration of, for example, an administered drug, or other compound in a sample obtained from a subject. The sample may be, e.g., a blood sample, a saliva sample, a urine sample, or other sample obtained from the patient. A level may be measured from a fraction of a sample. For example, a level may be measured in the plasma fraction of a blood sample; may be measured in a serum fraction of a blood sample; or, in embodiments, may be measured in whole blood.

[0044] Hypercortisolism, often referred to as Cushing’s syndrome, is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. Cushing’s syndrome caused by a pituitary tumor is referred to as Cushing’s Disease. In the United States, an estimated 20,000 patients have Cushing’s syndrome, with about 3,000 new patients diagnosed each year. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Hypercortisolism can affect every organ system and can be lethal if not treated effectively.

[0045] As used herein, the term “glucocorticoid receptor” (“GR”) refers to the type II GR, a family of intracellular receptors which specifically bind to cortisol and / or cortisol analogs such as dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 200535283-292). The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR and mutated GR.

[0046] The term “glucocorticoid receptor modulator” (GRM) refers to any compound which modulates GC binding to GR, or which modulates any biological response associated with the binding of GR to an agonist. For example, a GRM that acts as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK). A GRM that acts as an antagonist, such as mifepristone, decreases the activity of tyrosine aminotransferase (TAT) in HepG2 cells.TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0047] As used herein, “relacorilant” refers to the heteroaryl-ketone fused azadecalin 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.8,859,774), also known as “CORT125134”, which has the following structure:. Relacorilant is described in U.S. Patent 8,859,774, hereby incorporated by reference in its entirety.

[0048] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients such as the said compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, in combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are meant to encompass any composition made by admixing compounds of the present invention and their pharmaceutically acceptable carriers.

[0049] “Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptable carrier” refer to a substance that aids the administration of an active agent to – and absorption by – a subject and can be included in the compositions of the present invention without causing asignificant adverse toxicological effect on the patient. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidant agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically-acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavors and colors, and the like. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in preparing and administering relacorilant as disclosed herein. PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[0050] In embodiments, pharmaceutical compositions useful for the methods and uses disclosed herein include relacorilant. Such pharmaceutical compositions may include a pharmaceutically acceptable excipient and relacorilant. Formulations including relacorilant include those formulations disclosed in U.S. Patent 11,464,764 and in U.S. Patent 11,935,626 (the contents of which patents are hereby incorporated by reference in their entireties).

[0051] Relacorilant can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Relacorilant may also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.

[0052] For preparing pharmaceutical compositions containing relacorilant, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation andadministration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").

[0053] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of relacorilant. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0054] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 6000 mg, most typically 50 mg to 500 mg. Suitable dosages also include about (in milligrams (mg)) 1, 5, 10, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or even greater amounts mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0055] In some embodiments, relacorilant is administered in one dose. In other embodiments, relacorilant is administered in more than one dose, e.g., 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, or more. In some cases, the doses are of an equivalent amount. In other cases, the doses are of different amounts. The doses can increase or taper over the duration of administration.

[0056] Any suitable relacorilant dose may be used in the methods disclosed herein. Suitable relacorilant doses include, for example, 25 mg, 50 mg, 75, mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg per day. In some embodiments, the daily dose of relacorlant is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 5060, 70, 80, 90 or 100 mg / kg / day. In some cases, relacorilant is administrated 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. Relacorilant can be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses. In embodiments, relacorilant is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0057] The duration of relacorilant treatment can vary according to the severity of the condition in a subject and the subject's response to GRMs or SGRMs. Generally administrationof relacorilant should be continued until clinically significant reduction or amelioration is observed. Treatment with relacorilant in accordance with the methods and uses disclosed herein may last for as long as two years, three years, or even longer, as needed. In some embodiments, relacorilant may be administered for a period of about 1 week to 104 weeks (2 years), or more, and may be administered for an indefinite number of years as needed. In some embodiments, relacorilant may be administered for about 6 weeks to 80 weeks, most typically about 9 to 60 weeks, or more, and may be administered for an indefinite number of weeks, as needed. Suitable periods of administration also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable periods of administration also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 4850, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 8890, 95, 96, 100, and 104 weeks.

[0058] In some embodiments, relacorilant administration is not continuous and can be stopped for one or more periods of time, followed by one or more periods of time where administration resumes. Suitable periods where administration stops include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 100 weeks. Suitable periods where administration stops 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, 4850, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 8890, 95, 96, and 100 weeks.

[0059] Relacorilant can be used in combination with other active agents. In some embodiments, co-administration includes administering relacorilant within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration includes administering relacorilant while a patient has another drug in their body, and include administering another drug while a patient has relacorilant in their body.EXAMPLES

[0060] The following examples are provided by way of illustration only and not by way of limitation. Those of skill will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar results. EXAMPLE 1 in vitro Studies

[0061] In summary, relacorilant was tested as an inhibitor of human P-gp using Caco-2 cells and digoxin as a substrate. P-gp-mediated Basolateral-to-Apical (B-to-A) trans-cellular digoxin transport was measured in the presence of increasing concentrations of relacorilant or verapamil as a positive control inhibitor. relacorilant showed concentration-dependent P-gp inhibition with IC50value of 1.3 M.

[0062] The assay was performed as follows: inhibition of P-gp by relacorilant was measured in Caco-2 cells using 10 M digoxin as a P-gp substrate. Caco-2 cells were seeded at 40,000 cells per well in 24 well HTS transwells (Corning) on 0.4 m polycarbonate membranes for 22 days in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% (v / v) fetal bovine serum, 100 units / mL Penicillin, 0.1 mg / mL Streptomycin, 2 mM L-glutamine and 1% non- essential amino acids in a humidified atmosphere containing 95% air / 5% CO2. The cell culture medium was replaced every 2 to 3 days until use at 21 – 25 days of barrier differentiation. Trans- epithelial electrical resistance (TEER) was measured using a Chopstick electrode set pre assay as a quality control. On the day of use the apical (A) and basolateral (B) surfaces of the cells were washed twice for 1 minute at room temperature with Hank’s Balanced Salt Solution (HBSS) containing 5 mM glucose, 0.1% bovine serum albumin and 25 mM HEPES, pH 7.4, 37°C (‘buffer’). A third, 30 minute wash at 37°C was performed with buffer containing either no inhibitor, Verapamil (P-gp inhibitor) or relacorilant on both the apical and basolateral surfaces at the desired concentrations. The wash buffer was removed and 750 L of buffer containing substrate (digoxin) with the above inhibitor was then added to the basolateral compartment.250 L buffer without or with the inhibitor was added to the apical compartment and the plates were returned to the incubator for two hours. After 2 hours 100 L of buffer from both the basolateral and apical compartments was sampled and added to methanol containing an internal standard (0.67 M tolbutamide), mixed and placed at -20°C for 2 hours to quench and allow protein to precipitate. Buffer samples containing substrate were also quenched at t=0 hour to allow a percentage recovery calculation. Matrix matched standard curves were prepared to allowquantification. All samples were centrifuged at 2500 x g, 4°C for 20 minutes and the resulting supernatants were transferred to a fresh 96-well plate, compatible with the autosampler (Greiner). The plate was sealed with a pre-slit silicone mat and analyzed by LC-MS / MS using matrix-matched standard curves. Transporter-mediated transport was calculated by subtracting passive permeability, i.e. non-specific binding / permeability in the presence of the highest concentration of the positive control inhibitor. Transport in the presence of inhibitors was expressed as a percentage of uninhibited controls. IC50values were estimated by fitting inhibitory concentration-effect curve data to a modified version of the Hill equationin which E is the effect, is the upper asymptote (maximum effect), [I] is the inhibitor concentration and nH is the slope. All data is presented as mean of triplicate determinations and error bars represent one standard deviation.

[0063] The propensity for relacorilant to act as substrate for P-gp was investigated. Results indicated relacorilant does not act as a substrate for P-gp.

[0064] Relacorilant was investigated as an inhibitor of P-gp. Relacorilant exhibits inhibition of P-gp with an IC50 value of 1.3 μM. EXAMPLE 2 in vivo Studies

[0065] Relacorilant was investigated as an inhibitor of P-gp in vivo in a single center, open- label, non-randomized, single sequence, drug-drug interaction (DDI) study in fasted healthy male and female subjects, between the ages of 18 and 55 years with a body mass index of 19–32 kilograms per square meter (kg / m2) and body weight 50 kg (110 lb). Subjects were administered a single dose of dabigatran etexilate, a P-gp substrate, 75 mg in the absence (Day 1) or presence (Day 12) of steady state plasma exposures of relacorilant 400 mg, which was administered once daily (QD) on Days 3 to 13. The 400 mg QD dose of relacorilant used in this study is the highest proposed clinical dose. The subjects remained on site until Day 14. Blood samples were collected at 0 (pre-dose) through 48 hours (h) post Day 1 and Day 12 dabigatran etexilate dose administration. Plasma concentrations of free and total dabigatran were determined using a validated LC-MS / MS method. Pharmacokinetic parameters for free and total dabigatranwere estimated using a Phoenix®noncompartmental analysis method and a formal statistical analysis was performed on exposure parameters. Safety was also assessed. Results

[0066] Doses of 75 mg dabigatran etexilate and doses of 400 mg relacorilant administered QD were tolerated under the conditions of the study. Of the 30 subjects enrolled in the study, 24 completed the study, 5 withdrew consent due to a treatment emergent adverse event (TEAE) (upper abdominal pain in 4 subjects, nausea in 1 subject, and back pain in 1 subject), and 1 was withdrawn due to a TEAE which occurred prior to relacorilant dosing. The most commonly reported TEAEs considered to be related to relacorilant were upper abdominal pain, back pain, headache and nausea and were mild or moderate in severity. There was no meaningful change to the relacorilant safety profile when administered with dabigatran etexilate, compared with relacorilant administered alone. No new safety findings were identified.

[0067] Following a single oral dose of 75 mg dabigatran etexilate alone in the absence of relacorilant (n= 30) on Day 1, adjusted geometric mean plasma exposures (based on Cmax and AUC0-inf) of free dabigatran were 76.5 ng / mL and 522 ng*h / mL, respectively; and of total dabigatran were 90.6 ng / mL and 629 ng*h / mL, respectively. Following a single oral dose of 75 mg dabigatran etexilate and 400 mg QD dose of relacorilant (n= 24) on Day 12, the geometric mean plasma exposures (based on Cmaxand AUC0-inf) of free dabigatran were 83.8 ng / mL and 503 ng*h / mL, respectively; and of total dabigatran were 111 ng / mL and 673 ng*h / mL, respectively.

[0068] A formal primary statistical analysis showed that the geometric mean ratio (%GMR) and 90% confidence intervals (CI) of Cmax and AUC0-inf for free dabigatran, in the presence of relacorilant, were 113 (92.1-139) and 102 (84.2-124), respectively, compared to dabigatran etexilate dosed alone in the absence of relacorilant. Similarly, the %GMR and CI of Cmax and AUC0-inf for total dabigatran, in the presence of relacorilant, were 124 (99.5-155) and 111 (91- 135), respectively, compared to dabigatran etexilate dosed alone in the absence of relacorilant. These data are tabulated in the Fig. 1.

[0069] Graphical representations of the plasma free dabigatran concentrations are shown in FIG. 2. Fig. 2 presents a Log10 / Linear graph illustrating plasma free dabigatran concentrations following the administration of single oral doses of 75 mg dabigatran etexilate either alone (onDay 1) or in the presence of relacorilant (Day 12). 400 mg doses of relacorilant were given once daily for each of 11 days prior to the measurements made on Day 12. Data points are geometric mean values, error bars are ± geometric Standard Deviation.

[0070] Graphical representations of the plasma total dabigatran concentrations are shown in FIG. 3. FIG.3 presents a Log10 / Linear graph illustrating plasma total dabigatran concentrations following the administration of single oral doses of 75 mg dabigatran etexilate either alone (on Day 1) or in the presence of relacorilant (Day 12). 400 mg doses of relacorilant were given once daily for each of 11 days prior to the measurements made on Day 12. Data points are geometric mean values, error bars are ± geometric Standard Deviation. Summary

[0071] Following a single oral dose of 75 mg dabigatran etexilate, the free and total dabigatran plasma exposures (AUC0-inf) were similar in the absence and presence of 400 mg QD relacorilant. There were small numeric increases in free and total dabigatran plasma Cmax in the presence of relacorilant compared to dabigatran alone; these increases were not considered to be clinically relevant. Overall, 400 mg QD relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures, suggesting no dose adjustments are needed for P-gp substrates upon coadministration with relacorilant.

[0072] All patents, patent publications, publications, and patent applications cited in this specification are hereby incorporated by reference herein in their entireties as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In addition, although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WE CLAIM:

1. A method of treating a patient suffering from a disorder amenable to treatment by relacorilant, the method comprising administering to said patient an effective amount of relacorilant concomitantly with an effective amount of a P-glycoprotein (P-gp) substrate drug, Wherein said effective amount of said P-gp substrate drug is the same as the effective amount of said P-gp substrate drug when said P-gp substrate drug is administered in the absence of relacorilant, effective to treat said disorder amenable to treatment by relacorilant.

2. The method of claim 1, wherein said disorder amenable to treatment by relacorilant is a disorder selected from hypercortisolism, hyperglycemia, hypertension, and a solid tumor in combination with chemotherapy or immunotherapy agents.

3. The method of claim 1, wherein said P-gp substrate drug is selected from the group consisting of dabigatran etexilate, digoxin, edoxaban, fexofenadine, clarithromycin, cyclosporin, colchicine, diltiazem, erythromycin, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine.

4. The method of claim 2, wherein the disorder is hypercortisolism.

5. The method of claim 4, wherein said hypercortisolism is Cushing’s syndrome.

6. The method of claim 4, wherein said hypercortisolism is Cushing’s Disease.

7. The method of claim 2, wherein the disorder is hyperglycemia.

8. The method of claim 2, wherein the disorder is hypertension.

9. The method of claim 2, wherein the disorder is a solid tumor, and said treatment comprises a combination treatment with a chemotherapy agent.

10. The method of claim 2, wherein the disorder is a solid tumor, and said treatment comprises a combination treatment with an immunotherapy agent.

11. The use of relacorilant for treating a disorder amenable to treatment by relacorilant, wherein said treatment comprises administering an effective amount of relacorilantto a patient suffering from said disorder amenable to treatment by relacorilant concomitantly with an effective amount of a P-glycoprotein (P-gp) substrate drug, Wherein said effective amount of said P-gp substrate drug is the same as the effective amount of said P-gp substrate drug when said P-gp substrate drug is administered in the absence of relacorilant.

12. The use of claim 11, wherein said disorder amenable to treatment by relacorilant is a disorder selected from hypercortisolism, hyperglycemia, hypertension, and a solid tumor in combination with chemotherapy or immunotherapy agents.

13. The use of claim 11, wherein said P-gp substrate drug is selected from the group consisting of dabigatran etexilate, digoxin, edoxaban, fexofenadine, clarithromycin, cyclosporin, colchicine, diltiazem, erythromycin, omeprazole, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil, and duloxetine.

14. The use of claim 12, wherein the disorder is hypercortisolism.

15. The use of claim 14, wherein the disorder is Cushing’s syndrome.

16. The use of claim 14, wherein said hypercortisolism is Cushing’s Disease.

17. The use of claim 12, wherein the disorder is hyperglycemia.

18. The use of claim 12, wherein the disorder is hypertension.

19. The use of claim 12, wherein the disorder is a solid tumor, and said treatment comprises a combination treatment with a chemotherapy agent.

20. The use of claim 12, wherein the disorder is a solid tumor, and said treatment comprises a combination treatment with an immunotherapy agent.

21. The use of any of claims 11 to 20, wherein the effective amount of relacorilant is selected from 10 mg, 25 mg, 50 mg, 75, mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

22. The use of claim 21, wherein said administration of relacorilant is oral administration.

23. The use of claim 21, wherein the said administration of relacorilant is daily administration.

24. The use of claim 21, wherein said relacorilant administration is administration with food.

25. The use of claim 21, wherein said relacorilant administration is administration without food.

26. The method of any of claims 1 to 10, wherein the effective amount of relacorilant is selected from 10 mg, 25 mg, 50 mg, 75, mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

27. The method of claim 26, wherein said administration of relacorilant is oral administration.

28. The method of claim 26, wherein the said administration of relacorilant is daily administration.

29. The method of claim 26, wherein said relacorilant administration is administration with food.

30. The method of claim 26, wherein said relacorilant administration is administration without food.

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