Combination administration of the glucocorticoid receptor modulator relacorilant and paclitaxel, a dual substrate of CYP2C8 and CYP3A4

Abstract

Many drugs useful for cancer treatment are metabolized by CYP2C8 enzymes, CYP3A4 enzymes, or both. The effects of the co-administration of paclitaxel and relacorilant, drugs used for cancer treatment that are substrates for both CYP2C8 and CYP3A4, are disclosed herein. Relacorilant potently inhibited CYP2C8 and CYP3A4 in in vitro tests, which would have increased paclitaxel plasma exposure in vivo by more than fivefold, thus indicating that the dose of paclitaxel should be significantly reduced when relacorilant and paclitaxel are co-administered. Surprisingly, paclitaxel plasma exposure increased by only about 80% instead of the expected more than fivefold increase anticipated with the co-administration of relacorilant and paclitaxel. The applicant discloses a safe method of co-administering relacorilant and paclitaxel by reducing the dose of paclitaxel to about half the dose of paclitaxel used when paclitaxel is administered alone. Relacorilant and this reduced dose of paclitaxel may be co-administered to treat cancer, e.g., ovarian cancer or pancreatic cancer.

Description

Background Technology

[0001] The presence of two drugs simultaneously or nearly simultaneously (e.g., concomitant use) in a subject can alter the effects of one, the other, or both of the drugs. These alterations are referred to as drug-drug interactions (DDIs). For example, the required dose of a drug is often significantly influenced by the amount and rate at which it is broken down and eliminated from the body (e.g., by the action of the liver or kidneys). However, the presence of a second drug acting in the body, for instance, by the liver and kidneys, can significantly affect the rate and amount of breakdown of the first drug, potentially increasing or decreasing the amount of the first drug remaining in the body at a given time compared to the amount that would have been present at that time in the absence of the second drug. Thus, for instance, the presence of a second drug that acts as an inhibitor of the enzyme metabolizing the first drug will inhibit the metabolism of the first drug and, consequently, often increase the effective dose of the first drug. If the first drug has toxic side effects, this increase in the effective dose of the first drug can lead to dangerous toxicities that would not have been anticipated in the absence of the second drug.

[0002] The concomitant administration of different drugs often results in adverse effects because the metabolism and / or elimination of one drug is reduced or interfered with by the metabolism and / or elimination of the other drug(s); consequently, it can alter the effective concentrations of these drugs compared to their effective concentrations when administered alone. Therefore, the concomitant administration of drugs may increase the risk of toxic effects of one or both of the concomitantly administered drugs.

[0003] Cytochrome P450 (abbreviated as CYP or P450) enzymes are hemoproteins composed of approximately 500 amino acids. Fifty-seven human functional CYP genes have been identified. Human CYP genes are classified into 18 families, denoted by Roman numerals, and 44 subfamilies, denoted by capital letters. The classification is based on the amino acid sequence identity of the encoded proteins (Nelson, 2009). Eleven enzymes derived from CYP families 1, 2, and 3 (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) contribute primarily to drug and chemical metabolism (Guengerich 208; Zanger and Schwab 2013). These enzymes contribute to the biotransformation of approximately 70% of clinically used drugs. Generally, these enzymes provide elimination mechanisms for drugs and other xenobiotics, facilitating their removal from the body via urine and / or bile. CYPs represent one of the most versatile enzymes in nature in relation to their broad substrate profiles and types of biotransformation reactions. Individual CYP enzymes exhibit distinct, but sometimes overlapping, substrate and inhibitor selectivity. Since many drugs inhibit the activity of one or more CYP enzymes, they have the potential to cause drug-drug interactions. Therefore, a therapeutic dose of a first drug metabolized by a CYP enzyme can become a toxic dose when administered with a second drug that inhibits the same CYP enzyme, as this results in an increase in the level of the first drug (compared to the level obtained with the same dose of the first drug in the absence of the second drug) because the CYP enzyme activity on the first drug will be reduced by the presence of the second drug.

[0004] Many therapeutically important drugs are metabolized by CYP enzymes. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone (Beckman et al., Pharmacol Rev 68:168-241 (2016)). DDI between CYP2C8 substrates and other drugs can be significant; Gibbons et al. recommend reducing the dose of enzalutamide to about half of the single-drug dose when used in combination with a potent CYP2C8 inhibitor (Clin Pharmacokinet (2015) 54:1057-1069). Substrates metabolized by CYP3A4 include, for example, midazolam, triazolam, and paclitaxel. Paclitaxel (Taxol) is widely used as a chemotherapy agent to treat various types of cancer, including ovarian cancer, breast cancer, prostate cancer, esophageal cancer, melanoma, and other solid tumor cancers. The primary elimination pathway of paclitaxel is through metabolism by both CYP3A4 and CYP2C8. Drug-drug interactions with clopidogrel (a potent CYP2C8 inhibitor) can decrease paclitaxel clearance, thereby increasing the risk of paclitaxel toxicity; therefore, “caution should be exercised when co-administration of paclitaxel and clopidogrel cannot be avoided” (Bergman et al., Br J Clin Pharmacol (2015) 81(2):313-315). The label for paclitaxel includes a warning that caution should be exercised when paclitaxel is co-administered with CYP2C8 and / or CYP3A4 inhibitors.Nab-paclitaxel is an albumin-bound form of paclitaxel with fewer side effects than paclitaxel.

[0005] Relacorilant (see Fig. 1; also see Hunt et al., J. Med. Chem. 60:3405-3421 (2017)) is a selective non-steroidal modulator of glucocorticoid receptors, which is being investigated in clinical trials in patients with Cushing's syndrome and various types of cancer, including ovarian and pancreatic cancer.

[0006] summation

[0007] Many therapeutic drugs are substrates of CYP2C8, CYP3A4, or both enzymes; when a first drug metabolized by these CYP enzymes is co-administered with a second drug that is an inhibitor of a CYP enzyme, the safe dose of the first drug may become a toxic dose. If the primary elimination pathway of a therapeutic drug involves metabolism by both CYP2C8 and CYP3A4 enzymes, administration of a co-administered drug that inhibits both CYP2C8 and CYP3A4 is expected to significantly increase plasma levels of the therapeutic drug by blocking only its elimination pathway. Co-administration with dual inhibitors of CYP2C8 and CYP3A4 will result in larger-scale drug-drug interactions (DDI) compared to co-administration with inhibitors of only one of the enzymes. In vitro studies are used to identify drug combinations expected to experience these negative DDIs.

[0008] Relacorilant is considered useful for treating many disorders, including cancer and hypercortisolism. Relacorilant is also considered useful for combination therapy for cancer and the treatment of hypercortisolism. In in vitro tests, relacorilant was found to be a potent inhibitor of CYP2C8 (IC2C8). 50 It is 0.21 μM) and a potent inhibitor of CYP3A4 (IC 0.21 μM). 50It was demonstrated that (1.32 μM). This potent dual inhibition of both CYP2C8 and CYP3A4 is expected to increase plasma exposure of dual CYP2C8 and CYP3A4 substrates by more than fivefold when co-administered with relacorilant. Therefore, it was expected that a significant dose reduction would be required for dual CYP2C8 and CYP3A4 substrates (e.g., paclitaxel) when administered in combination with relacorilant.

[0009] When co-administered with relacorilant, this potent inhibition of CYP2C8 and CYP3A4 by relacorilant is expected to increase plasma exposure of paclitaxel by blocking the primary elimination pathway of paclitaxel through CYP2C8- and CYP3A4-mediated metabolism. Therefore, it was expected that a significant reduction in the dose of paclitaxel would be required when administered in combination with relacorilant. Based on the expected effects of relacorilant on paclitaxel metabolism, co-administration of paclitaxel and relacorilant was expected to potentially reduce the dose of paclitaxel by more than fivefold compared to when paclitaxel is administered with relacorilant.

[0010] Surprisingly, the applicant discovered that the co-administration of paclitaxel and relacorilant does not require a significant reduction in the dose of paclitaxel. The applicant discovered that when paclitaxel is co-administered with relacorilant, the plasma level of paclitaxel does not increase by more than five times (compared to the plasma level when the same dose of paclitaxel is administered alone), and surprisingly, increases by only about 80%.

[0011] Therefore, based on the potent in vitro dual inhibition of CYP2C8 and CYP3A4, a significant increase in paclitaxel exposure of more than fivefold is expected when paclitaxel is co-administered with relacorilant. Surprisingly, the applicant discloses herein that relacorilant and paclitaxel can be co-administered with only a slight reduction in the paclitaxel dose. Thus, in contrast to the expected requirement for a reduction in the paclitaxel dose of more than fivefold, the applicant indicates that relacorilant can be safely administered with paclitaxel, wherein the dose of paclitaxel is the same as the dose of paclitaxel administered in the absence of relacorilant (typically about 100-125 mg / m²). 2 The applicant discloses herein that the reduction is approximately 20% to approximately 35% (e.g., approximately 20%, or approximately 25%, or approximately 30%, or approximately 35%) compared to ). The applicant states that relacorilant can be safely administered with paclitaxel, wherein the dose of paclitaxel is the same as the dose of paclitaxel administered in the absence of relacorilant (typically about 100-125 mg / m²). 2 Approximately 80 mg / m² from ) 2 (e.g., approximately 65 mg / m² 2 , or about 70 mg / m² 2 , or about 75 mg / m² 2 , or about 80 mg / m² 2 , or about 85 mg / m² 2 , or about 90 mg / m² 2 , or about 95 mg / m² 2 The present invention discloses that it is reduced to ). In a specific example, paclitaxel is administered in the form of nab-paclitaxel. This combined administration of paclitaxel and relacorilant is considered safe for the subject and provides the subject with the therapeutic benefits of both drugs.

[0012] The method disclosed herein provides a safe method for administering drug combinations and dosages that were previously expected to be unsafe, thereby making the combination of paclitaxel and relacorilant safe and effective. This drug combination is believed to provide more effective treatment than treatment with only one of the drugs in the absence of the other. The remarkable ability to safely administer these drug combinations offers benefits including more effective treatment, the absence of previously expected side effects, and other advantages. Brief explanation of the drawing

[0013] Figure 1 shows the chemical structure of relacorylant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone). Specific details for implementing the invention

[0014] details

[0015] Based on standard in vitro test results, relacorilant was found to be a potent inhibitor of CYP2C8 and CYP3A4. These in vitro results suggested that co-administration of relacorilant would increase plasma levels of CYP2C8 and / or CYP3A4 substrates by more than fivefold. Paclitaxel is a substrate for both CYP2C8 and CYP3A4 metabolism. For this reason, co-administration of relacorilant and paclitaxel is expected to significantly increase paclitaxel concentrations beyond those obtained with paclitaxel monotherapy. Similar to the in vitro results, human clinical studies showed an eightfold increase in exposure to midazolam (a standard CYP3A4 substrate) when co-administered with relacorilant. Surprisingly, in a human clinical study conducted on healthy volunteers to evaluate the effect of relacorilant on the concentration of pioglitazone (a standard CYP2C8 substrate), no increase in pioglitazone concentration was observed. Also surprisingly, in a human study on cancer patients, the combination of paclitaxel and relacorilant was found to increase paclitaxel plasma levels by only about 80%, instead of the larger increase expected due to the in vitro potent dual inhibition of both CYP2C8 and CYP3A4.

[0016] The applicant discloses herein the surprising discovery that relacorilant can be safely co-administered with slightly dose-adjusted paclitaxel. This small dose adjustment was surprisingly smaller than anticipated based on the greater increase predicted by the in vitro potent dual inhibition of both CYP2C8 and CYP3A4. In a specific example, relacorilant and paclitaxel were combined at a paclitaxel dose of approximately 100 mg / m² required for paclitaxel monotherapy. 2 to about 125 mg / m² 2 From, the paclitaxel dose was approximately 80 mg / m² 2By reducing the dose, it can be co-administered to patients requiring treatment. Relacorilant and paclitaxel are the paclitaxel dose of approximately 100 mg / m² required for paclitaxel monotherapy for cancer. 2 to about 125 mg / m² 2 From, the paclitaxel dose was approximately 80 mg / m² 2 By reducing [the dose], it can be co-administered to treat cancers such as ovarian or pancreatic cancer, for example. This co-administration of relacorilant and paclitaxel provides the patient with therapeutically effective levels of both relacorilant and paclitaxel simultaneously, while avoiding overdose or toxic doses of each drug.

[0017] In a specific embodiment, the applicant discloses a method for treating cancer, said method for a patient requiring said cancer treatment

[0018] a) an effective dose of Relacorilant; and

[0019] b) comprising the step of administering an effective dose of paclitaxel, wherein the paclitaxel is approximately 100 mg / m² when administered without other drugs. 2 to about 125 mg / m² 2 It has a single drug dose, wherein the effective dose of paclitaxel is reduced by about 20% to about 35% from the single drug dose of paclitaxel when co-administered with relacorilant;

[0020] The above a) and b) are performed at an effective time to simultaneously provide the patient with an effective level of relacorilant and an effective level of paclitaxel, and

[0021] Cancer is treated by this.

[0022] In a specific example, the effective dose of paclitaxel is reduced by about 20%, or about 25%, or about 30%, or about 35% from the single-drug dose of paclitaxel when co-administered with relacorilant. For example, here the effective dose of paclitaxel is about 100 mg / m² 2In the case of a single drug dose, when co-administered with relacorilant, the reduced paclitaxel dose is decreased by approximately 20% to approximately 80 mg / m² 2 This can be. Here, the effective dose of paclitaxel is approximately 110 mg / m² 2 In the case of a single drug dose, when co-administered with relacorilant, the reduced paclitaxel dose is decreased by approximately 20% to approximately 88 mg / m² 2 This can be. Here, the effective dose of paclitaxel is approximately 120 mg / m² 2 In the case of a single drug dose, when co-administered with relacorilant, the reduced paclitaxel dose is decreased by approximately 20% to approximately 96 mg / m² 2 This can be. Here, the effective dose of paclitaxel is approximately 125 mg / m² 2 In the case of a single drug dose, when co-administered with relacorilant, the reduced paclitaxel dose is decreased by approximately 20% to about 100 mg / m² 2 This may be the case. As an additional example, the reduced paclitaxel dose here may be reduced by approximately 25% when co-administered with relacorilant, and approximately 100 mg / m² 2 The single drug dose of paclitaxel is approximately 75 mg / m² 2 It can be reduced to; approximately 110 mg / m² 2 The single drug dose of paclitaxel is approximately 83 mg / m² 2 It can be reduced to; approximately 120 mg / m² 2 The single drug dose of paclitaxel is approximately 90 mg / m² 2 It can be reduced to; approximately 125 mg / m² 2 The single drug dose of paclitaxel is approximately 94 mg / m² 2 It may be reduced to. Here, the paclitaxel dose may be reduced by approximately 30% when co-administered with relacorilant, and is approximately 100 mg / m² 2 The single drug dose of paclitaxel is approximately 70 mg / m² 2It can be reduced to; approximately 110 mg / m² 2 The single drug dose of paclitaxel is approximately 77 mg / m² 2 It can be reduced to; approximately 120 mg / m² 2 The single drug dose of paclitaxel is approximately 84 mg / m² 2 It can be reduced to; approximately 125 mg / m² 2 The single drug dose of paclitaxel is approximately 88 mg / m² 2 It may be reduced to. Here, the paclitaxel dose may be reduced by approximately 35% when co-administered with relacorilant, and is approximately 100 mg / m² 2 The single drug dose of paclitaxel is approximately 65 mg / m² 2 It can be reduced to; approximately 110 mg / m² 2 The single drug dose of paclitaxel is approximately 72 mg / m² 2 It can be reduced to; approximately 120 mg / m² 2 The single drug dose of paclitaxel is approximately 78 mg / m² 2 It can be reduced to; approximately 125 mg / m² 2 The single drug dose of paclitaxel is approximately 81 mg / m² 2 It can be reduced to. In a specific example, paclitaxel is administered in the form of nab-paclitaxel.

[0023] In a specific embodiment, the applicant discloses a method for treating cancer, said method for a patient requiring said cancer treatment

[0024] a) an effective dose of Relacorilant; and

[0025] b) comprising the step of administering an effective dose of paclitaxel, wherein the paclitaxel is approximately 100 mg / m² when administered without other drugs. 2 to about 125 mg / m² 2 It has a single drug dose, and the effective dose of paclitaxel is approximately 65 mg / m² when co-administered with relacorilant. 2 to about 95 mg / m² 2And;

[0026] The above a) and b) are performed at an effective time to simultaneously provide the patient with an effective level of relacorilant and an effective level of paclitaxel, and

[0027] Cancer is treated by this.

[0028] In a specific example, the effective dose of paclitaxel is approximately 65 mg / m² 2 , or about 70 mg / m² 2 , or about 75 mg / m² 2 , or about 80 mg / m² 2 , or about 85 mg / m² 2 , or about 90 mg / m² 2 , or about 95 mg / m² 2 is. In a specific example, the effective dose of paclitaxel is 80 mg / m² 2 This is a specific example. In this example, paclitaxel is administered in the form of nab-paclitaxel.

[0029] In a specific example, the cancer is ovarian cancer; or pancreatic cancer; or prostate cancer, esophageal cancer, melanoma and / or other solid tumor cancer.

[0030] The applicant's remarkable discovery is believed to apply to patients suffering from diseases or disorders treatable with paclitaxel and relacorilant, such as cancer. For example, patients receiving paclitaxel for the treatment of ovarian or pancreatic cancer may benefit from combination therapy with paclitaxel and relacorilant, and while receiving relacorilant, the paclitaxel dose is approximately 100 mg / m² 2 to about 125 mg / m² 2 From approximately 80 mg / m² (the paclitaxel dose required for paclitaxel monotherapy) 2 Paclitaxel can be continued by reducing it.

[0031] In a specific example, relacorilant is administered orally. In a specific example, relacorilant is administered on a daily basis; for example, in a specific example, relacorilant is administered once a day. In a specific example, relacorilant is administered with a meal. "With a meal" administration means that the patient has started eating within 30 minutes or 1 hour of the time when relacorilant is administered. For example, relacorilant may be administered to the patient with a meal, or immediately after the patient has started eating (e.g., within 30 minutes).

[0032] In an alternative embodiment, Relacorilant is administered to a fasting patient, that is, a patient who has not eaten for at least 1 hour, or at least 2 hours, or longer before administering Relacorilant. For example, Relacorilant may be administered to a fasting patient in the morning, that is, a patient who has not yet had breakfast and has not eaten since dinner the previous day.

[0033] In a specific example, relacorilant is administered daily at a daily dose of about 1 to 100 mg / kg / day, preferably about 1 to 20 mg / kg / day. In a specific example, the daily dose of relacorilant is about 10 to about 2000 milligrams (mg) of relacorilant, or about 50 to about 1500 mg, or about 100 to about 1000 mg. In a specific example, the daily dose of relacorilant may be about 10 mg, or 15 mg, or 20 mg, or 25 mg, or 50 mg, or 100 mg, or 150 mg, or 200 mg, or 250 mg, or 300 mg, or 350 mg, or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg, or 750 mg, or 800 mg, or 850 mg, or 900 mg, or 950 mg. In a specific example, the effective dose of relacorilant is 75 mg / day (milligrams per day) to 200 mg / day and may be selected from 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, and 200 mg / day. In a specific example, the effective dose of relacorilant is 100 mg / day, 125 mg / day, or 150 mg / day. In a specific example, the effective dose of relacorilant is 100 mg / day, 125 mg / day, or 150 mg / day. In a specific example, the dose of relacorilant may be adjusted from the initial dose during the course of treatment (e.g., may be increased).

[0034] In a specific example, paclitaxel is administered as nab-paclitaxel. In a specific example, the dose of nab-paclitaxel is about 60 to about 95 mg / m² 2 , for example, about 70 to 90 mg / m² 2It can be administered by intravenous infusion. For example, nab-paclitaxel is 80 mg / m² by intravenous (iv) infusion. 2 It may be administered at a dose. Such infusions may be administered intermittently. For example, such infusions may be administered on days 1, 8, and 15 of each 28-day cycle. In a specific example, the dose of nab-paclitaxel is 60 mg / m² administered by IV infusion on days 1, 8, and 15 of each 28-day cycle. 2 is. In a specific example, relacorilant is administered daily. In a specific example, relacorilant may be administered in a dose of about 75 to about 250 mg, for example, 100 mg, or 125 mg, or 150 mg, or 175 mg, or 200 mg. In a specific example, relacorilant is administered daily at a dose of 100 mg. In a specific example, relacorilant is administered daily at a dose of 150 mg. In a specific example, for example, paclitaxel is nab-paclitaxel, and relacorilant is administered daily at a dose of 150 mg. In a specific example, for example, paclitaxel is nab-paclitaxel, and relacorilant is administered daily at a dose of 200 mg. In a specific example, for example, paclitaxel is nab-paclitaxel, and relacorilant is administered intermittently at a dose of 150 mg (the day before, the day of, and the day after the nab-paclitaxel injection). In a specific example, for example, paclitaxel is nab-paclitaxel, and relacorilant is administered intermittently at a dose of 200 mg (the day before, the day of, and the day after the nab-paclitaxel injection).

[0035] definition

[0036] As used herein, the term "patient" refers to a human being who is receiving, is scheduled to receive, or has received medical treatment for a disease or medical condition.

[0037] As used herein, the terms “administer,” “administering,” “administered,” or “administration” refer to providing a compound or composition (e.g., as described herein) to a subject or patient. Administration may be performed by oral administration (i.e., administering the compound or composition to the subject through the mouth in the form of a pill, capsule, liquid, or other form suitable for administration through the mouth). Oral administration typically involves swallowing a pill, capsule, liquid, or other preparation. Oral administration may include buccal administration (placing the compound or composition in the mouth, e.g., under the tongue, where it is absorbed).

[0038] Other examples of modes of administration include, for example, by injection, i.e., by a needle, microneedle, or pressure injector, or by other means that puncture the skin or force the compound or composition through the skin of the subject. Injection may be performed intravenously (i.e., into the vein); intra-arterially (i.e., into the artery); intraperitoneally (i.e., into the peritoneum); intramuscularly (i.e., into the muscle); or by other routes of injection. Routes of administration may also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneously (e.g., by absorption into the skin from an implant containing the compound or composition), or other routes.

[0039] As used herein, the terms "effective amount" or "therapeutic amount" refer to an amount of a drug effective for treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, "therapeutically effective amount" or "effective amount" may refer to an amount of an agent or pharmaceutical composition useful for producing a detectable therapeutic or inhibitory effect. Such effect may be detected by any analytical method known in the art.

[0040] As used herein, the terms “co-administration,” “concurrent administration,” “combination administration,” “combination therapy,” and similar terms refer to the administration of at least two agents to a subject to treat a disease or pathological condition. The two agents may be administered simultaneously, or sequentially in any order during all or part of the treatment period. At least two agents may be administered according to the same or different dosage regimens. These agents may include, for example, relacorilant and other drugs, which may be, for example, drugs useful for treating hypercortisolism, drugs useful for treating cancer, or other therapeutic agents. In some cases, one agent is administered according to a scheduled dosage regimen, while the other agent is administered intermittently. In some cases, the two agents are administered intermittently. In some embodiments, one agent may be administered daily, and the other agent may be administered every 2, 3, or 4 days.

[0041] As used herein, the terms “intermittent” and “intermittently” refer to the administration of a dose of a drug or compound (“drug”) that is not administered daily; for example, administering a dose of the compound every other day constitutes intermittent administration of the compound. Any administration schedule less frequent than daily administration is intermittent administration; additional examples of intermittent administration include, but are not limited to, administration every 2 days, or every 3 days, or every 4 days. Intermittent administration also includes, as additional examples, administration of the first drug on the day before, the day of, and the day after administration of the second drug; administration of the first drug on days 1, 15, and 28 of a repeated cycle of drug administration (which may include administration of the second drug on a different administration schedule); and other schedules and sequences of drug administration.

[0042] As used herein, the term “pharmaceuticalally acceptable carrier” is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, absorption retardants, and analogs suitable for administering the medicine. Therapeutic agents, such as relacorilant, pioglitazone, rosiglitazone, enzalutamide, etc., are typically administered as capsules, tablets, or other formulations comprising an active agent and one or more pharmaceutically acceptable carriers. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in the composition is considered, except where any conventional media or agent is not suitable for the active compound. A supplementary active agent may also be incorporated into the composition.

[0043] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates the binding of GC to GR, or modulates any biological response associated with the binding of GR to an agonist. For example, GRMs acting as agonists, such as dexamethasone, increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatic hepatocellular carcinoma cell line; ECACC, UK). GRMs acting as antagonists, such as mifepristone, decrease the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity is [referred to in] ​​Literature A. Ali et al. It can be measured as summarized in , J. Med. Chem., 2004, 47, 2441-2452.

[0044] Rellacorrylant (((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone)) is a GRM. Rellacorrylant is described in Example 18 of U.S. Patent No. 8,859,774 (incorporated herein by reference).

[0045] As used herein, the term "CYP2C8" refers to the cytochrome P450 enzyme subtype 2C8. In humans, the most common form has 490 amino acids and has UniProtKB accession number P10632.2. The gene encoding CYP2C8 has Gene ID 1558.

[0046] CYP2C8 substrate drugs include amodiaquin, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone (Beckman et al., Pharmacol Rev 68:168-241 (2016)).

[0047] As used herein, the term "CYP3A4" refers to the cytochrome P450 enzyme subtype 3A4. In humans, the common isoform has 503 amino acids (isoform 1) or 502 amino acids (isoform 2), and the protein has UniProtKB accession number P10632.2. The gene encoding CYP3A4 has Gene ID 1576.

[0048] CYP3A4 substrate drugs include paclitaxel, midazolam, and triazolam.

[0049] Example 1. In vitro CYP inhibition analysis

[0050] E. coli ( E.coli Cytochrome P450 (CYP) isoforms CYP2B6, CYP2C8, and CYP3A5, which are heterologously expressed in ), were obtained from Cypex and mixed to produce a 3-CYP mixture. In individual analyses, isoforms for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are heterologously expressed in E. coli and were obtained from Cypex as a custom-made mixture of five isoforms. For each isoform, a selective and FDA-approved substrate was used for its K m It was presented in the reaction at a nearby concentration.

[0051] A cocktail of relacorylant (final concentration range 0.032–10 μM, 1% DMSO) or control CYP inhibitors was added to reaction tubes in a 96-well plate format. The CYP mixture and CYP substrate cocktail were added, and the tubes were heated for 3 minutes while mixing in BioShake IQ (37°C, 1500 rpm). NADPH (final concentration 1 mM) was added, and the mixture was incubated for 10 minutes. Then, methanol containing an internal standard (1 μM tolbutamide) was added to all samples, mixed, and the reaction was quenched at -20°C for ≥ 1 hour to allow the protein to precipitate.

[0052] All samples were centrifuged (2500 xg, 20 min, 4°C). The supernatant was transferred to a new 96-well plate compatible with an autosampler. The plate was sealed with a pre-slit silicone mat, and metabolites were analyzed by LC-MS / MS.

[0053] Control group CYP inhibitor (IC 50 - An appropriate concentration range, final analysis concentration (1% DMSO) was added as a cocktail. In Analysis 1, the cocktail consisted of CYP2B6, ticlopidine; CYP2C8, quercetin; and CYP3A5, ketoconazole. In Analysis 1, the cocktail consisted of CYP1A2, α-naphthoflavone; CYP2C9, sulfaphenazole; CYP2C19, tranylcypromine; CYP2D6, quinidine; and CYP3A4, ketoconazole.

[0054] In Analysis 1, the final concentration of the 3-CYP mixture was 18 pmol / mL for CYP2B6 (where pmol is picomoles), 1 pmol / mL for CYP2C, and 5 pmol / mL for CYP3A5. In Analysis 2, the final concentration of the 5-CYP mixture was 32.5 pmol / mL for each enzyme evaluated (i.e., CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). In Analysis 1, the CYP substrate cocktail contained the following components: CYP2B6, bupropion; CYP2C8, amodiaquine; CYP3A5, midazolam. The solvent for all stock solutions was methanol, and the final concentration of methanol in the analysis was 0.625%. The measured metabolites were CYP2B6, hydroxybupropion; CYP2C8, N-desethyl amodiaquine; and CYP3A5, 1'-hydroxymidazolam.

[0055] In Analysis 2, the CYP substrate cocktail included the following components: CYP1A2, tacrine; CYP2C9, diclofenac; CYP2C19, (S)mephenytoin; CYP2D6, ubfuralol; CYP3A4, midazolam. The metabolites measured were CYP1A2, 1-hydroxytacrine; CYP2C9, 4'-hydroxydiclofenac; CYP2C19, 4'-hydroxymephenytoin; CYP2D6, hydroxyubfuralol; and CYP3A4, 1'-hydroxymidazolam.

[0056] All reactions were performed in duplicate at 37°C and in 0.1 M phosphate buffer (pH 7.4). In Analysis 1, the final protein concentration was 0.06 mg / ml. In Analysis 2, the final protein concentration was 0.12 mg / ml.

[0057] Data processing

[0058] Process data and the result into an IC 50Reported as a value (concentration causing 50% inhibition of the reaction), generated from a pseudo-Hill plot, and the slope and y-intercept are IC according to the following equation 50 It was used to calculate.

[0059]

[0060] In Analysis 1, Relacorilant had an average IC50 of 0.21 μM in this analysis. 50 CYP2C8 was inhibited by the value. In Analysis 2, relacorilant had an average IC50 of 1.32 μM. 50 CYP3A4 was inhibited by the value.

[0061] Relacorilant has an average IC50 of 0.21 μM. 50 Based on in vitro data demonstrating potent inhibition of CYP2C8, co-administration of therapeutic concentrations of relacorilant with CYP28 substrates is expected to result in a greater than fivefold increase in plasma exposure of CYP2C8 substrates compared to administration of the CYP2C8 substrate alone. In vitro CYP2C8 results, and relacorilant with an average IC50 of 1.32 μM. 50 Based on in vitro data showing that it potently inhibits CYP3CA4, co-administration of therapeutic concentrations of relacorilant is expected to increase plasma exposure of both CYP2C8 and CYP3A4 substrates by more than five times compared to administration of the substrate alone.

[0062] Example 2. Clinical drug-drug interaction study in healthy volunteers

[0063] An open-label crossover study was conducted in healthy subjects to determine the effect of relacorilant on plasma exposure to midazolam, a known substrate of CYP3A4, and pioglitazone, a known substrate of CYP2C8. A single dose of 2.5 mg of midazolam was administered alone, and intensive pharmacokinetic (PK) samples were collected before administration (hour 0) and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours after administration. On the next day, a single dose of pioglitazone 15 mg was administered alone, and concentrated PK samples were collected before administration (hour 0) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, and 72 hours after administration. Then, relacorilant 350 mg was administered once daily for 9 consecutive days. On the 10th day of once-daily relacorilant administration, a single dose of midazolam 2.5 mg was administered in combination with relacorilant 350 mg, and concentrated PK samples were collected again from before administration to 24 hours after administration. On the next day, a single dose of 15 mg of pioglitazone was administered in combination with 350 mg of relacorilant, and intensive pharmacokinetic (PK) samples were collected again from before administration up to 72 hours after administration. Plasma concentrations of midazolam and its metabolite 1-OH midazolam, and pioglitazone and its metabolite pioglitazone M4 were evaluated by validated bioanalytical assays at each time point of administration of midazolam or pioglitazone.

[0064] PK results showed that once-daily administration of relacorilant compared to midazolam monotherapy reduced plasma exposure (AUC) to midazolam and its metabolites infIt was shown that it increased ) by >8-fold, confirming potent inhibition of CYP3A4 in vivo (Table 1). However, PK results also showed that once-daily administration of relacorilant did not increase plasma exposure to pioglitazone or its metabolites, indicating that relacorilant has no inhibitory effect on CYP2C8 (Table 2). Although inhibition of CYP2C8 by relacorilant was previously observed in vitro, results from clinical drug interaction studies demonstrated that relacorilant does not inhibit CYP2C8 in vivo.

[0065] Statistical comparison of pharmacokinetic parameters of plasma midazolam and its metabolites: Day 14 (Treatment D) vs. Day 1 (Treatment A) (PK group) Parameters (Units) Test (14th) Treatment D Reference (1 day) Treatment A Proportion of geometric LSMs (%) 90% confidence interval Geometric LSM n Geometric LSM n Midazolam C max (ng / mL) 36.85 26 11.85 27 310.98 271.96 - 355.61 AUC 0-tz (ng·h / mL) 271.5 26 30.91 27 878.43 762.70 - 1011.7 AUC inf (ng·h / mL) 294.7 26 33.01 25 892.81 774.67 - 1029.0 1-OH midazolam C max (ng / mL) 6.657 26 4.038 27 164.86 139.84 - 194.35 AUC 0-tz (ng·h / mL) 74.56 26 9.360 27 796.64 695.61 - 912.35 AUC inf (ng·h / mL) 83.72 26 10.28 26 814.51 712.14 - 931.60

[0066] ANOVA, Analysis of Variance; AUC inf , AUC extrapolated from time 0 to infinity; AUC 0-tz , AUC from time 0 to the time of the final measurable concentration; C max , maximum plasma concentration; CV%, coefficient of variation; LSM, least squares mean.

[0067] Treatment A: A single oral dose of 2.5 mg of midazolam hydrochloride administered on Day 1 (see reference).

[0068] Treatment D: A single oral dose of 2.5 mg of midazolam hydrochloride and 350 mg of relacorilant administered on day 14 (test).

[0069] The parameters were ln-transformed before analysis.

[0070] The geometric LSM was calculated by exponentializing the LSM from ANOVA.

[0071] Ratio of geometric LSMs = 100*(test / reference); where test is treatment d and reference is treatment A.

[0072] Statistical comparison of pharmacokinetic parameters of plasma pioglitazone and its metabolites: Day 15 (Treatment E) vs. Day 2 (Treatment B) (PK group) Parameters (Units) Test (15 days) Treatment E Reference (2 days) Treatment B Proportion of geometric LSMs (%) 90% confidence interval Geometric LSM n Geometric LSM n Pioglitazone C max (ng / mL) 376.5 26 483.8 27 77.82 69.65 - 86.96 AUC 0-tz (ng·h / mL) 3953 26 5290 27 74.71 68.06 - 82.02 AUC inf (ng·h / mL) 4047 25 5408 27 74.83 68.11 - 82.21 Pioglitazone M4 C max (ng / mL) 253.9 26 237.3 27 106.99 99.70 - 114.81 AUC 0-tz (ng·h / mL) 10460 26 10460 27 99.97 94.80 - 105.43 AUC inf (ng·h / mL) 12590 25 12890 26 97.68 92.98 - 102.62

[0073] ANOVA, Analysis of Variance; AUCinf , AUC extrapolated from time 0 to infinity; AUC 0-tz , AUC from time 0 to the time of the final measurable concentration; C max , maximum plasma concentration; CV%, coefficient of variation; LSM, least squares mean.

[0074] Treatment B: A single oral dose of 15 mg of pioglitazone hydrochloride (see reference).

[0075] Treatment E: A single oral dose of 15 mg of pioglitazone hydrochloride and 350 mg of relacorilant administered on day 15, followed by an oral dose of 350 mg of relacorilant administered QD on days 16 and 17 (test).

[0076] The parameters were ln-transformed before analysis.

[0077] The geometric LSM was calculated by exponentializing the LSM from ANOVA.

[0078] Ratio of geometric LSMs = 100*(test / reference); where test is treatment E and reference is treatment B.

[0079] Example 3. Administration of Relacorilant and nab-paclitaxel to a patient with advanced pancreatic cancer

[0080] The combination of relacorilant and nab-paclitaxel was evaluated in patients with advanced solid tumors. Since the elimination of nab-paclitaxel is primarily mediated by CYP3A4 and CYP2C8, this study was specifically designed to evaluate the potential for drug-drug interactions by including a one-week introduction of nab-paclitaxel (single administration of nab-paclitaxel on Day 1) and a one-week introduction of relacorilant (daily relacorilant for 7 days) prior to the initiation of Cycle 1. Interactions were anticipated because relacorilant was found to be a potent dual inhibitor of CYP3A and CYP2C8 in vitro. The PK results of the introduction in this study showed an increase in nab-paclitaxel exposure (AUC ~80% higher) when administered in combination with relacorilant compared to nab-paclitaxel alone (Table 3). This small increase in AUC is surprisingly low considering the larger increase predicted by the in vitro strong double inhibition of both CYP2C8 and CYP3A4.

[0081] Mean pharmacokinetic parameters for Nab-paclitaxel alone or in combination with relacorilant PK parameters Nab-paclitaxel 80 mg / m² 2 single Average (%CV) (Day 1 of introduction) N=14 Nab-paclitaxel 80 mg / m² combined with relacorilant 100 mg 2 Average (%CV) (Cycle 1, Day 8) N=24 AUC (ng·h / mL) 2530 (28) 4550 (97) C max (ng / mL) 3250 (45) 3230 (81)

[0082] Source: Research CORT125134-550

[0083] All patents, patent publications, publications, and patent applications cited herein are incorporated herein by reference in their entirety, as indicated by each individual publication or patent application being incorporated by reference in a specific and individual manner. Furthermore, although the foregoing invention has been described in some detail through examples and embodiments for clarity of understanding, it will be apparent to those skilled in the art, in light of the teachings of the present invention, that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

Claims

Claim 1 delete Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 A pharmaceutical composition for treating cancer comprises a) an effective dose of 75 mg to 250 mg of relacorilant; and b) an effective dose of paclitaxel, wherein the relacorilant and paclitaxel are administered to a patient requiring cancer treatment; and wherein the paclitaxel is 100 mg / m² when administered without other drugs. 2 to 125 mg / m² 2 It has a single drug dose, and the effective dose of paclitaxel is 60 mg / m² when co-administered with relacorilant. 2 to 75 mg / m² 2 And; a) and b) above are administered at an effective time to simultaneously provide the patient with an effective level of relacorilant and an effective level of paclitaxel, thereby treating the cancer, and is a pharmaceutical composition. Claim 18 A pharmaceutical composition according to claim 17, wherein the paclitaxel is in the form of nab-paclitaxel. Claim 19 In claim 17, the effective dose of paclitaxel is paclitaxel 60 mg / m² 2 , 65 mg / m 2 , 70 mg / m 2 , and 75 mg / m² 2 A pharmaceutical composition selected from. Claim 20 A pharmaceutical composition according to claim 17, wherein the effective dose of relacorilant is 70 mg to 100 mg of relacorilant. Claim 21 delete Claim 22 A pharmaceutical composition according to claim 17, wherein the cancer comprises a solid tumor. Claim 23 A pharmaceutical composition according to claim 17, wherein the cancer is selected from ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, and melanoma. Claim 24 A pharmaceutical composition according to claim 17, wherein the cancer is ovarian cancer or pancreatic cancer. Claim 25 A pharmaceutical composition according to claim 17, wherein the relacorilant is administered orally. Claim 26 A pharmaceutical composition according to claim 17, wherein the relacorilant is administered daily. Claim 27 A pharmaceutical composition according to claim 17, wherein the relacorilant is administered intermittently. Claim 28 A pharmaceutical composition according to claim 26, wherein the relacorilant is administered on the day before, the day of, and the day after administration of paclitaxel. Claim 29 In claim 17, the paclitaxel is in the form of nab-paclitaxel, and the relacorilant is 75 mg, 100 mg, and 150 mg of relacorilant on the day before, the day of, and the day after administration of nab-paclitaxel. A pharmaceutical composition administered intermittently at a dose selected from 175 mg and 200 mg. Claim 30 In claim 28, the dose of relacorilant and the dose of paclitaxel are administered according to a 28-day schedule, the paclitaxel is in the form of nab-paclitaxel, and the dose of nab-paclitaxel is nab-paclitaxel 60 mg / m² 2 , 65 mg / m 2 , 70 mg / m 2 , 72 mg / m 2 , and 75 mg / m² 2 A pharmaceutical composition selected from and administered by intravenous infusion on days 1, 8, and 15 of each 28-day cycle.

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