US-12616685-B2 - Concomitant administration of glucocorticoid receptor modulator relacorilant and CYP2C9 substrates

Abstract

Relacorilant is useful in the treatment of hypercortisolism and cancer. Many drugs useful in treating hypercortisolism or cancer are metabolized by CYP2C9 enzymes. The effects of concomitant administration of relacorilant and a CYP2C9 substrate are disclosed herein. Relacorilant potently inhibited CYP2C9 in an in vitro test, indicating that co-administration of relacorilant and a CYP2C9 substrate would be expected to increase the CYP2C9 substrate plasma exposure more than five-fold in vivo. Significant reductions in CYP2C9 substrate doses would be expected to be required when administered with relacorilant. Surprisingly, no such increase in plasma exposure was seen in human studies. Applicant discloses that relacorilant may be safely co-administered with unmodified doses of a CYP2C9 substrate such as, e.g., tolbutamide, glimepiride, and glipizide. Relacorilant and unmodified doses of CYP2C9 substrate such as tolbutamide, glimepiride, and glipizide may be co-administered to treat hypercortisolism, or may be co-administered to a cancer patient.

Inventors

• Hazel Hunt
• Joseph Custodio

Assignees

• CORCEPT THERAPEUTICS INCORPORATED

Dates

Publication Date

20260505

Application Date

20210526

Claims (9)

1. 1 . A method of treating a disorder selected from the group consisting of i) hypercortisolism, ii) a symptom associated with hypercortisolism in a patient suffering from hypercortisolism, iii) cancer, and iv) a symptom associated with cancer in a cancer patient, said treatment comprising combined administration of tolbutamide and relacorilant to a patient in need of treatment for said disorder, the method comprising administering to said patient in need of treatment for said disorder, without increased tolbutamide plasma exposure to said patient: a) a 350 milligrams (mg) dose of relacorilant; and b) 500 mg dose of tolbutamide, wherein said combined administration of relacorilant and tolbutamide does not increase the tolbutamide AUC inf as compared to the tolbutamide AUC inf when administered in the absence of relacorilant, and reduces the tolbutamide C max by an amount that is about 31% of the tolbutamide C max when it is administered in the absence of relacorilant; Whereby the disorder is treated.
2. 2 . The method of claim 1 , wherein said disorder is selected from the group consisting of hypercortisolism and a symptom associated with hypercortisolism in a patient suffering from hypercortisolism.
3. 3 . The method of claim 2 , wherein said symptom associated with hypercortisolism in a patient suffering from hypercortisolism is selected from the group consisting of diabetes, hypertension, hyperglycemia, abnormal body fat, excessive body fat, moon-face, and abnormal blood clotting.
4. 4 . The method of claim 3 , wherein said symptom associated with hypercortisolism in a patient suffering from hypercortisolism is diabetes.
5. 5 . The method of claim 1 , wherein said disorder is cancer, or a symptom associated with cancer in a cancer patient.
6. 6 . The method of claim 5 , wherein the cancer is ovarian cancer or pancreatic cancer.
7. 7 . The method of claim 5 , wherein said cancer patient is receiving paclitaxel or nab-paclitaxel.
8. 8 . The concomitant use of relacorilant and the CYP2C9 substrate tolbutamide in a concomitant treatment, said concomitant treatment comprising concomitant administration of 350 milligrams (mg) of relacorilant and 500 mg of tolbutamide to a patient suffering from and in need of treatment for a disorder, for the treatment of said disorder without increased tolbutamide plasma exposure to said patient, wherein the disorder is selected from the group consisting of hypercortisolism, a symptom associated with hypercortisolism, cancer, and a symptom associated with cancer, wherein said concomitant administration of relacorilant and tolbutamide does not increase the tolbutamide AUC inf as compared to the tolbutamide AUC inf when administered in the absence of relacorilant, and reduces the tolbutamide C max by an amount that is about 31% of the tolbutamide C max when it is administered in the absence of relacorilant, whereby the patient is treated for the disorder.
9. 9 . The use of claim 8 , wherein said disorder is selected from the group consisting of hypercortisolism and a symptom associated with hypercortisolism.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/030,809, filed May 27, 2020, which application is hereby incorporated by reference herein in its entirety. BACKGROUND The simultaneous, or nearly simultaneous (e.g., concomitant) presence of two drugs in a subject may alter the effects of one or the other, or both, drugs. Such alterations are termed drug-drug interactions (DDIs). For example, the required dose of a drug is often strongly affected by the amount and rate of its degradation in, and elimination from, the body (e.g., by liver or kidney action). However, the presence of a second drug in the body, which is also being acted upon, e.g., by the liver and kidney, can have significant effects on the amount and rate of degradation of the first drug, and can increase or decrease the amount of the first drug that remains in the body at a given time as compared to the amount that would have been present at that time in the absence of the second drug. Thus, for example, the presence of a second drug that is an inhibitor of an enzyme that metabolizes a first drug will inhibit the metabolism of the first drug and thus can often increase the effective dose of the first drug. Where the first drug has toxic side effects, such an increase in effective dose of the first drug may lead to dangerous toxicity that would not have been expected were the second drug not present. Concomitant administration of different drugs often leads to adverse effects since the metabolism and/or elimination of each drug may reduce or interfere with the metabolism and/or elimination of the other drug(s), thus altering the effective concentrations of those drugs as compared to the effective concentrations of those drugs when administered alone. Thus, concomitant administration of drugs may increase the risk of toxic effects of one or both of the co-administered drugs. Cytochrome P450 (abbreviated as CYP or P450) enzymes are hemoproteins of approximately 500 amino acids. Fifty-seven human functional CYP genes have been identified. The human CYP genes are classified into 18 families, designated by a Roman numeral, and 44 subfamilies designated by a capital letter. Classification is based on the amino acid sequence identity of the encoded proteins (Nelson, 2009). Eleven enzymes from CYP families 1, 2 and 3 (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) primarily contribute 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 a clearance mechanism for drugs and other xenobiotics and facilitate elimination from the body in urine and/or bile. CYP represents one of nature's most versatile enzymes with respect to its broad substrate profile and types of biotransformation reactions. The individual CYP enzymes exhibit distinct, but sometimes overlapping, substrate and inhibitor selectivities. Many drugs inhibit the activity of one or more CYP enzymes, and thus have the potential to cause a drug-drug interaction. Thus, a therapeutic dose of a first drug that is metabolized by a CYP enzyme may become a toxic dose when the first drug is administered with a second drug that inhibits that same CYP enzyme, since the CYP enzyme action on the first drug will be reduced by the presence of the second drug, leading to increased levels of the first drug (as compared to the levels obtained by the same dose of the first drug in the absence of the second drug). Many therapeutically important drugs are metabolized by the CYP2C9 enzyme. CYP2C9 substrate drugs include, for example, tolbutamide, glimepiride, glipizide, warfarin, benzbromarone, celecoxib, ibuprofen, lornoxicam, meloxicam, and piroxicam. For example, the CYP2C9 substrate tolbutamide (used in treating diabetes) is metabolized by CYP2C9; administration of tolbutamide along with the CYP2C9 inhibitor sulfaphenazole to human subjects led to a more than 5-fold increase in the plasma level of tolbutamide (measured as area under the curve (AUC); Perkins et al., Eur J Drug Metab Pharmacokinet 43(3):355-367 (2018)). Citing similar data regarding tolbutamide, Miners et al. indicated that the current practice is to “individualise” the dose of tolbutamide when used with CYP2C9 substrates (Br J Pharmacol 45:525-538 (2998)). Relacorilant (see FIG. 1; see also Hunt et al., J. Med. Chem. 60:3405-3421 (2017)) is a selective, non-steroidal modulator of the glucocorticoid receptor that is being investigated in clinical trials in patients with Cushing's syndrome and in patients with various types of cancer including, e.g., pancreatic cancer or ovarian cancer. SUMMARY Many therapeutic drugs are substrates of CYP2C9 enzymes; an otherwise safe dose of a first drug metabolized by CYP2C9 may be a toxic dose when concomitantly administered with a