Methods for treating diseases with levocetconazole

Abstract

To provide a pharmaceutical composition for treating hypercortisolism in a subject of Cushing's syndrome.SOLUTION: A pharmaceutical composition contains levoketoconazole or a pharmaceutically acceptable salt thereof, and is administered to a subject in need thereof in a therapeutically effective amount. The pharmaceutical composition is administered with a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof. The subject also has type 2 diabetes and has had previous surgery or radiation to treat Cushing's syndrome. The therapeutically effective amount of the pharmaceutical composition is determined via a titration scheme including dose escalation of the pharmaceutical composition. When the subject experiences a dose limitation event, metformin or a pharmaceutically acceptable salt thereof is administered at a dose that is less than the therapeutically effective amount. The dose limitation event is reduction of a fasting blood glucose level, an abnormal renal function, a low vitamin B-12 level or any combination thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 813,399, filed March 4, 2019, the entire disclosure of which is incorporated by reference for all purposes. [Background technology]

[0002] Endogenous Cushing's disease is a rare, serious, and potentially fatal endocrine disorder caused by excessive exposure of organs to cortisol. In approximately 80% of patients, Cushing's syndrome results from excessive secretion of adrenocorticotropic hormone (ACTH), most commonly via a pituitary corticotropin adenoma and less frequently via an extrapituitary tumor (ectopic ACTH syndrome) or, in rare cases, an ectopic corticotropin-releasing hormone-secreting tumor. In the remaining 20% ​​of patients, Cushing's syndrome is ACTH-independent and is caused by excessive cortisol secretion due to a unilateral adrenocortical tumor, bilateral adrenal hyperplasia, or dysplasia.

[0003] Nizoral® (ketoconazole) is approved in the United States as an antifungal agent for certain systemic and refractory cutaneous fungal infections. Ketoconazole HRA® contains ketoconazole and is registered in several countries outside the United States for the treatment of Cushing's syndrome. Ketoconazole reduces or inhibits adrenal steroidogenesis by inhibiting several adrenal steroidogenic enzymes, including CYP17A1 (also known as 17α-hydroxylase) and CYP11B1 (also known as mitochondrial 11β-hydroxylase). A direct effect on ectopic ACTH has been observed in vitro. The efficacy of ketoconazole in the treatment of Cushing's syndrome has not been the subject of large-scale prospective clinical trials, but it has been the subject of several small, open-label studies and larger retrospective case series. Ketoconazole has been reported to normalize hypercortisolism in 30–70% of patients and reduce complications of excess cortisol, including diabetes and hypertension, as well as other signs and symptoms of Cushing's syndrome.

[0004] However, ketoconazole carries several known risks, including liver toxicity. High transaminase levels are common. Ketoconazole also strongly inhibits drug-metabolizing enzymes, including CYP3A4, and is associated with significant potential drug interactions, including those that increase the risk of QT prolongation. Despite the availability of two FDA-approved medications, ketoconazole continues to be commonly used off-label to treat Cushing's syndrome in the United States and appears to be the most frequently prescribed medical therapy for Cushing's syndrome, reflecting a persistent need not addressed by approved therapies.

[0005] Levocetoconazole (Recorlev™, COR-003, 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(IH-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl]piperazine) is an investigational cortisol synthesis inhibitor. Levocetoconazole is the 2S,4R enantiomer of ketoconazole. Nonclinical and clinical data suggest that, compared with the 2R,4S enantiomer of ketoconazole, levocetoconazole more potently inhibits cortisol synthesis and achieves higher plasma concentrations following ketoconazole administration. Summary of the Invention [Means for solving the problem]

[0006] Methods for treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer are provided, the methods comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also co-administered a therapeutically effective amount of a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, The therapeutically effective amount of the MATE1 substrate or the OCT2 substrate is reduced compared to a subject not administered levocetconazole, or a pharmaceutically acceptable salt thereof.

[0007] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is co-administered a therapeutically effective amount of a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, the method comprising: reducing the amount of a MATE1 substrate or an OCT2 substrate administered to the subject; subsequently initiating administration of a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme.

[0008] In some embodiments, decreasing the amount of the MATE1 substrate or the OCT2 substrate being administered to the subject comprises ceasing administration of the MATE1 substrate or the OCT2 substrate.

[0009] Also provided is a method for treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also co-administered a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, The therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof, is reduced compared to a subject not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, reducing the amount of metformin being administered to the subject comprises discontinuing administration of metformin.

[0011] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is co-administered a therapeutically effective amount of metformin, the method comprising: reducing the amount of metformin being administered to the subject; and subsequently initiating administration of a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme.

[0012] Also provided is a method for treating a disorder selected from Cushing's disease, syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme; Subsequently, determining that the patient should begin treatment with a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or the OCT2 substrate is administered in an amount less than would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0013] Also provided is a method for treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme; Subsequently, determining that the patient should begin treatment with metformin, wherein the metformin is administered in an amount less than would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the starting dose is less than the amount that would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof. In some embodiments, the starting dose is increased by smaller increments (e.g., 250 mg) than the amount that would be used in a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof (e.g., 500 mg).

[0015] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is also administered metformin, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, Administration of levocetconazole, or a pharmaceutically acceptable salt thereof, increases systemic exposure to metformin by approximately two-fold.

[0016] These and other aspects of the present invention will become apparent upon reference to the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds, and / or compositions, each of which is incorporated herein by reference in its entirety. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description When introducing elements of the disclosure or embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are inclusive and mean that there may be additional elements other than the listed elements.

[0018] The term "and / or," when appearing in a list of two or more items, means that any of the listed items may be used by itself or in combination with one or more of the listed items. For example, the phrase "A and / or B" means either or both of A and B, i.e., A alone, B alone, or a combination of A and B. The phrase "A, B, and / or C" is intended to mean A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0019] When a range of values ​​is disclosed, and the notation "n1... to n2" or "between n1... and n2" is used (where n1 and n2 are numbers), unless otherwise stated, this notation is intended to include itself and the numbers in the range therebetween. The range may be integer or continuous between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, compare the range "1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and all to any number of significant figures therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0020] The term "about" modifies the numerical value that it modifies and denotes such value as variable within a tolerance. When a tolerance, such as the standard deviation for an average value given in a chart or table of data, is not cited, the term "about" means a range that encompasses the cited value and any range encompassed by rounding up or down on that value, taking into account significant digits.

[0021] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the last element of any such definition is the one that is attached to the parent moiety. For example, the composite group alkylamido represents an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group.

[0022] The term "disease" as used herein is generally synonymous with, and intended to be used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all of these reflect an abnormal condition of the human or animal body or one of its parts in which normal functioning is impaired, is typically manifested by distinct signs and symptoms, and reduces the lifespan or quality of life of the human or animal.

[0023] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes substantially simultaneous coadministration of these therapeutic agents, for example, in a single capsule with a fixed ratio of active ingredients, or in multiple separate capsules for each active ingredient. In addition, such administration also includes sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0024] The phrase "therapeutically effective" is intended to modify the amount of active ingredient used in the treatment of a disease or disorder or the achievement of a clinical endpoint.

[0025] The term "therapeutically acceptable" refers to compounds that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, that meet an ideal benefit / risk ratio, and that are effective for their intended use.

[0026] As used herein, reference to "treatment" of a patient is intended to include prevention. Treatment may also be prophylactic in nature, i.e., include prevention of disease. Prevention of disease may include complete protection from disease, as in the case of preventing infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease may not mean complete elimination of any effects associated with the disease at any level, but may mean prevention of disease symptoms to a clinically significant or detectable level. Prevention of disease may also mean preventing disease progression to a late stage of the disease. In certain embodiments, prevention of disease may include prevention of intermittent attacks and prevention of permanent states of muscle weakness, e.g., prevention of irreversible states of functional impairment due to an underlying disease.

[0027] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0028] As used herein, a patient is said to "tolerate" a dose of a compound if administering that dose to the patient does not result in unacceptable adverse events or an unacceptable combination of adverse events.Those skilled in the art will recognize that tolerance is a subjective measure, and what can be tolerated by one patient may not be tolerated by another patient.For example, one patient may not be able to tolerate headache, while a second patient may be able to tolerate headache but not be able to tolerate vomit, while a third patient may be able to tolerate either headache alone or vomit alone, but the patient may not be able to tolerate the combination of headache and vomit, even if the severity of each is less than that experienced alone.

[0029] As used herein, an "adverse event" is an untoward medical occurrence associated with treatment with a pharmaceutical product.

[0030] As used herein, the term "hormone sensitive cancer" refers to any cancer that can be affected by hormones; hormones typically increase the growth of hormone sensitive cancers.

[0031] As used herein, "up-titrating" a compound refers to increasing the amount of the compound to achieve a therapeutic effect that occurs before a patient's dose-limiting intolerance. Up-titrating can be accomplished in one or more dose increments, which can be the same or different.

[0032] The compounds disclosed herein may exist as therapeutically acceptable salts. The present disclosure includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts may also be formed and may be pharmaceutically acceptable.

[0033] The term "therapeutically acceptable salt," as used herein, refers to a salt or zwitterionic form of a compound disclosed herein that is water- or oil-soluble or dispersible and therapeutically acceptable as defined herein. Salts can be prepared during the final isolation and purification of the compound, or can be prepared separately by reacting the free base form of the appropriate compound with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, and the like. The salts include methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordinating a compound with an alkali metal or alkaline earth ion. Thus, the present disclosure contemplates sodium, potassium, magnesium, calcium, and the like salts of the compounds disclosed herein.

[0034] Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0035] Salts of compounds can be made by reacting the free base form of the appropriate compound with a suitable acid.

[0036] Metformin refers to N,N-dimethylimidodicarbonimidediamide hydrochloride. Formulations of metformin have previously been reported in the FDA-approved drug label GLUCOPHAGE as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

[0037] GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 662.88 mg, and 779.86 mg of metformin base, respectively. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating of the 500 mg and 850 mg tablets contains hypromellose, and the coating of the 1000 mg tablet contains hypromellose and polyethylene glycol. GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride, which is equivalent to 389.93 mg and 584.90 mg of metformin base, respectively. GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients hypromellose, microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate. GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients hypromellose, sodium carboxymethylcellulose, magnesium stearate and iron oxide pigment red.

[0038] The standard dosage for metformin is: Adult Dosage for Glucophage: Starting dose: 500 mg orally twice daily or 850 mg once daily with food Give in divided doses, increasing the dose in 500 mg increments weekly or 850 mg increments every 2 weeks to a maximum dose of 2550 mg / day Doses greater than 2000 mg may be better tolerated when given three times daily with meals GLUCOPHAGE XR Adult Dosage: Starting dose: 500 mg orally once daily with dinner Increase the dose in 500 mg increments each week to a maximum of 2000 mg once daily with dinner Patients receiving GLUCOPHAGE may exchange for up to 2000 mg of GLUCOPHAGE XR once daily at the same total daily dose. GLUCOPHAGE Pediatric Dosage: Starting dose: 500 mg orally twice daily with meals Give in divided doses twice daily, increasing the dose in 500 mg increments weekly to a maximum of 2000 mg / day

[0039] An oral solution of metformin is also approved, containing 500 mg of metformin hydrochloride per 5 mL and the following inactive ingredients: calcium saccharin, potassium bicarbonate, xylitol, hydrochloric acid, purified water, and cherry flavor. The maximum recommended daily dose is 2550 mg (25.5 mL) for adults and 2000 mg (20 mL) for pediatric patients (10 to 16 years).

[0040] Methods for treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer are provided, the methods comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also co-administered a therapeutically effective amount of a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, The therapeutically effective amount of the MATE1 substrate or the OCT2 substrate is reduced compared to a subject not administered levocetconazole, or a pharmaceutically acceptable salt thereof.

[0041] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is co-administered a therapeutically effective amount of a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, the method comprising: reducing the amount of a MATE1 substrate or an OCT2 substrate administered to the subject; subsequently initiating administration of a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme.

[0042] In some embodiments, decreasing the amount of the MATE1 substrate or the OCT2 substrate being administered to the subject comprises ceasing administration of the MATE1 substrate or the OCT2 substrate.

[0043] Also provided is a method for treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also co-administered a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, The therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof, is reduced compared to a subject not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0044] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is co-administered a therapeutically effective amount of metformin, the method comprising: reducing the amount of metformin being administered to the subject; and subsequently initiating administration of a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme.

[0045] Also provided is a method for treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme; Subsequently, determining that the patient should begin treatment with a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or the OCT2 substrate is administered in an amount less than would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0046] Also provided is a method for treating a disorder selected from Cushing's disease, syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme; Subsequently, determining that the patient should begin treatment with a multidrug and toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or the OCT2 substrate is administered at a starting dose that is lower than the amount that would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the method further comprises increasing the starting dose by an amount less than that which would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises increasing the starting dose by 250 mg increments compared to the 500 mg increments that would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0048] Also provided is a method for treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer, the method comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme; Subsequently, determining that the patient should begin treatment with metformin, wherein the metformin is administered in an amount less than would be administered to a patient not receiving levocetconazole, or a pharmaceutically acceptable salt thereof.

[0049] Also provided is a method of treating a disorder selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous hypercortisolism, hypercortisolism, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject in need thereof, wherein the subject is also receiving metformin, comprising: administering a therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, to a subject in need thereof; The therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is determined via a titration scheme, Administration of levocetconazole, or a pharmaceutically acceptable salt thereof, increases systemic exposure to metformin by approximately two-fold.

[0050] In certain embodiments, the condition is Cushing's syndrome. In certain embodiments, the condition is cyclic Cushing's syndrome. In certain embodiments, the condition is persistent or recurrent Cushing's syndrome. In certain embodiments, the subject has had previous surgery or radiation to treat the subject's Cushing's syndrome. In certain embodiments, the subject has not had previous surgery or radiation to treat the subject's Cushing's syndrome. In certain embodiments, the condition is Cushing's disease.

[0051] In certain embodiments, the disease is exogenous hypercortisolism. In certain embodiments, the disease is hypercortisolism. In certain embodiments, the disease is hyperglycemia. In certain embodiments, the disease is multiple endocrine neoplasia type 1. In certain embodiments, the disease is McCune-Albright syndrome. In certain embodiments, the disease is Carney complex. In certain embodiments, the disease is congenital adrenal hyperplasia. In certain embodiments, the disease is precocious puberty.

[0052] In certain embodiments, the disease is a hormone-sensitive cancer. In certain embodiments, the disease is prostate cancer and other androgen-sensitive cancers. In certain embodiments, the disease is breast cancer, ovarian cancer, or another cancer that is sensitive to estrogen or progesterone.

[0053] In certain embodiments, the disease is a disorder amenable to treatment with levocetconazole, or a pharmaceutically acceptable salt thereof.

[0054] In certain embodiments, the titration scheme involves upward titration of levocetconazole, or a pharmaceutically acceptable salt thereof, until one or more of the following conditions are met: (1) the subject has an adequate response; (2) the highest labeled-specified dose is reached; or (3) a dose-limiting event occurs.

[0055] In certain embodiments, the titration scheme comprises: administering a first dose of levocetoconazole or a pharmaceutically acceptable salt thereof for a first period, for example, about 1 week; increasing the dose by an amount equal to an increment value; and determining whether the subject tolerates the increased dose; This cycle is repeated as long as the subject tolerates the increased dose, and the increment value in each cycle repetition is the same or different; if the subject does not tolerate the increased dose, the patient's dose is equal to the difference between the further increased dose and the increment value for the final cycle repetition. In certain embodiments, the initial dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg twice a day. In certain embodiments, the increment value is 150 mg.

[0056] In certain embodiments, the maximum protocol-specified dose is 1200 mg / day. In certain embodiments, subjects may receive doses of 150 mg twice daily to 600 mg twice daily. In certain embodiments, the dose is 150 mg once daily. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 150 mg to 1200 mg / day. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 150 mg once daily. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 150 mg twice daily. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 300 mg twice daily. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 450 mg twice daily. In certain embodiments, the therapeutically effective amount of levocetconazole, or a pharmaceutically acceptable salt thereof, is 600 mg twice daily.

[0057] In certain embodiments, the titration scheme includes an initial dose reduction. In certain embodiments, the initial dose of levocetconazole, or a pharmaceutically acceptable salt thereof, is 150 mg twice daily, and the reduced dose is 150 mg daily. In certain embodiments, after the initial dose reduction, if the subject tolerates the reduced dose, the dose is increased via the titration scheme described herein. In certain embodiments, administration is maintained at 150 mg daily.

[0058] In certain embodiments, the titration scheme involves up-titrating levocetconazole, or a pharmaceutically acceptable salt thereof, until the subject has a sufficient response. In certain embodiments, a sufficient response includes normalization of urinary cortisol (UFC) (e.g., 24-hour UFC, 4-hour UFC, 12-hour UFC, or other such UFC measurements), midnight salivary cortisol (LNSC), or multiply-sampled serum cortisol (MSSC). In certain embodiments, UFC, LNSC, or MSSC normalization includes at least a 50% decrease in mean UFC. In certain embodiments, a sufficient response is a decrease of less than 50% from baseline cortisol levels. In certain embodiments, up-titrating levocetconazole continues until at least two of the cortisol measurements selected from UFC, LNSC, and MSSC are below baseline cortisol levels, e.g., at least a 50% decrease from baseline cortisol levels. In certain embodiments, levocetconazole up-titration is stopped when UFC, LNSC, and MSSC normalize or fall below baseline cortisol levels, hi certain embodiments, a sufficient response includes an improvement in hypercortisolism as measured, for example, via hair cortisol or multiple sweat cortisol draws.

[0059] In certain embodiments, the titration scheme further comprises a maintenance phase in which the subject receives a fixed dose of a therapeutically effective amount of levocetconazole.

[0060] In certain embodiments, the titration scheme comprises upward titration of levocetoconazole, or a pharmaceutically acceptable salt thereof, until the subject experiences a dose-limiting event. In certain embodiments, the method further comprises decreasing the dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, after the subject experiences a dose-limiting event. In certain embodiments, the method further comprises temporarily discontinuing administration of levocetoconazole, or a pharmaceutically acceptable salt thereof, after the subject experiences a dose-limiting event until the dose-limiting event is reversed, and then resuming administration of levocetoconazole, or a pharmaceutically acceptable salt thereof, at the same or a reduced dose. In certain embodiments, administration of levocetoconazole, or a pharmaceutically acceptable salt thereof, is not resumed.

[0061] In certain embodiments, the dose-limiting event results from increased exposure to the MATE1 substrate or OCT2 substrate. In certain embodiments, the method further includes notifying the subject or a healthcare professional that co-administration of levocetconazole, or a pharmaceutically acceptable salt thereof, and a MATE1 substrate or an OCT2 substrate may result in increased exposure to the MATE1 substrate or an OCT2 substrate. In certain embodiments, the method further includes notifying the subject or a healthcare professional that co-administration of levocetconazole, or a pharmaceutically acceptable salt thereof, and a MATE1 substrate or an OCT2 substrate may result in one or more exposure-related adverse reactions associated with administration of the MATE1 substrate or an OCT2 substrate. In certain embodiments, the method further includes monitoring the serum concentration of the MATE1 substrate or the OCT2 substrate. In certain embodiments, the method further includes monitoring the subject for one or more exposure-related adverse reactions associated with administration of the MATE1 substrate or the OCT2 substrate.

[0062] In certain embodiments, the dose-limiting event is due to increased exposure to metformin. In certain embodiments, the method further includes notifying the subject or a healthcare professional that co-administration of levocetconazole, or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof, may result in increased exposure to metformin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further includes notifying the subject or a healthcare professional that co-administration of levocetconazole, or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof, may result in one or more exposure-related adverse reactions associated with metformin administration. In certain embodiments, the method further includes monitoring the serum concentration of metformin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further includes monitoring the subject for one or more exposure-related adverse reactions associated with metformin administration. These adverse reactions may be mild or moderate in severity. In certain embodiments, the method further comprises that the one or more exposure-related adverse reactions are selected from diarrhea, nausea / vomiting, flatulence, asthenia, dyspepsia, abdominal discomfort, lactic acidosis, and headache.

[0063] In certain embodiments, the dose-limiting event is a QTc prolongation event. In certain embodiments, a QTc prolongation event comprises at least one QTc value representing an increase of more than 60 msec from baseline. In certain embodiments, a QTc prolongation event comprises at least one confirmed QTc interval of more than 470 msec, or in certain embodiments, at least one confirmed QTc interval of more than 500 msec. In certain embodiments, a QTc prolongation event comprises an absolute QTc interval of more than 470 msec in men and more than 480 msec in women. In certain embodiments, a QTc prolongation event comprises an absolute QTc interval of more than 60 msec above baseline.

[0064] In certain embodiments, the method further comprises monitoring the effect on the QTc interval.

[0065] In certain embodiments, the dose-limiting event is elevated liver function tests (LFTs). In certain embodiments, LFTs include tests analyzing one or more of the following analytes in serum: alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), and / or bilirubin (unconjugated, conjugated, or total). In certain embodiments, elevated LFTs are at least 1.5 times the upper limit of normal of the reference range. In certain embodiments, elevated LFTs are at least 2 times the upper limit of normal of the reference range. In certain embodiments, elevation further includes an elevation of more than 1 time the upper limit of normal of the reference range in either ALT or AST. To that effect, normal ranges for a given analyte may vary based on testing methodology and from laboratory to laboratory. In certain embodiments, the method further includes monitoring liver function.

[0066] In certain embodiments, the dose-limiting event is an increased risk of lactic aldosis type B. In certain embodiments, the dose-limiting event is a blood pH below 7.35 and a lactate concentration above 5 mmol / L. In some embodiments, the subject also has a decreased serum bicarbonate concentration (e.g., below 22 mmol / L) and / or an anion gap above 12 meQ / L.

[0067] In certain embodiments, the dose limiting event is abnormal renal function. In certain embodiments, the method further comprises monitoring eGFR. In certain embodiments, abnormal renal function is ≥ 30 mL / min / 1.73 m 2 In certain embodiments, abnormal renal function includes an estimated glomerular filtration rate (eGFR) of less than 30-45 mL / min / 1.73 m 2 In certain embodiments, the eGFR is 35 mL / min / 1.73 m 2 If the blood glucose level drops below 0.5, the method further comprises discontinuing administration of metformin.

[0068] In certain embodiments, the dose limiting event is a decrease in fasting glucose levels, hi certain embodiments, the dose limiting event is the risk of further hypoglycemia.

[0069] In certain embodiments, the dose limiting event is anion gap acidosis. In certain embodiments, the dose limiting event is macrocytic anemia secondary to low vitamin B-12.

[0070] In certain embodiments, the MATE1 substrate is selected from the substrates shown below (or a pharmaceutically acceptable salt thereof):

[0071] [Table 1]

[0072] In certain embodiments, the MATE1 substrate is selected from cimetidine, abemaciclib, levofloxacin, ciprofloxacin, topotecan, metformin, cephalexin, acyclovir, cephradine, estrone sulfate, ganciclovir, guanidine, procainamide, and combinations thereof, or pharmaceutically acceptable salts thereof. In certain embodiments, the MATE1 substrate is metformin, or a pharmaceutically acceptable salt thereof.

[0073] In certain embodiments, the OCT2 substrate is selected from the substrates shown below (or a pharmaceutically acceptable salt thereof):

[0074] [Table 2]

[0075] In certain embodiments, the OCT2 substrate is selected from amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, and oxaliplatin, or a pharmaceutically acceptable salt thereof. In certain embodiments, the OCT2 substrate is metformin, or a pharmaceutically acceptable salt thereof.

[0076] In certain embodiments, the dose of the MATE1 substrate or OCT2 substrate is reduced. In certain embodiments, the dose of the MATE1 substrate or OCT2 substrate is reduced by at least 5%, e.g., at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90%. In certain embodiments, the administration frequency of the MATE1 substrate or OCT2 substrate is reduced. For example, if the dose is not reduced, the administration frequency can be extended from twice daily (BID) to once daily (QD), or every other day (QOD), etc.

[0077] In certain embodiments, the dose of metformin or a pharmaceutically acceptable salt thereof is reduced. In certain embodiments, the dose of metformin or a pharmaceutically acceptable salt thereof is reduced by at least 5%, for example, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90%. In certain embodiments, the administration frequency of metformin or a pharmaceutically acceptable salt thereof is reduced. For example, if the dose is not reduced, the administration frequency can be extended from twice a day (BID) to once a day (QD), or every other day (QOD), etc.

[0078] The disclosed compounds may be administered as raw chemicals, but can also be present as pharmaceutical formulations. Thus, provided herein are pharmaceutical formulations comprising one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Appropriate formulations depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as appropriate and as understood in the art. The pharmaceutical compositions disclosed herein can be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0079] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including transdermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein, or a pharmaceutically acceptable salt thereof (the "active ingredient"), with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0080] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent in a suitable machine. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0081] In some embodiments, the dosage form is suitable for oral administration and comprises one or more pharmaceutical excipients.In some embodiments, the unit dosage form is an immediate-release tablet comprising 150 mg of levocetconazole with microcrystalline cellulose, lactose, corn starch, colloidal silicon dioxide, and magnesium stearate.In some embodiments, the tablet is film-coated.

[0082] The compounds may be administered orally or via injection at doses of 0.1 to 500 mg / kg / day. The dose range for adult humans is generally 150 mg to 1.2 g / day. Tablets or other presentation forms provided in discrete units conveniently contain amounts of one or more compounds effective in such dosages, or multiples thereof; for example, a unit may contain from 150 mg to 1200 mg.

[0083] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented for illustrative purposes only and to assist those of ordinary skill in the art in using the present disclosure. The examples are not intended to limit the scope of the present disclosure in any way. [Example]

[0084] Example 1 Drug-Drug Interaction Studies Using MATE1 and OCT2 Substrates This study was designed to evaluate levocetconazole as an inhibitor of MATE1 or OCT2. Compounds that are substrates or inhibitors of transporters can be victims or perpetrators of drug-drug interactions. The experiment was performed as described in the FDA and EMA draft guidance document for Drug Interaction Studies (FDA 2017, EMA 2013). The probe substrate was [ 14 C] metformin.

[0085] Short-term stability studies were performed on test article solutions. Dose solutions of low and high test article concentrations (e.g., 0.03 and 50 μM) were prepared in each incubation medium and stored in the selected container type at room temperature and 37°C ± 2°C for 6 hours. After the applicable storage period, solutions of the same test article concentration were reprepared and analyzed along with previously stored samples to determine stability. Solutions were stable if the difference in mean response (e.g., area ratio) for fresh and stored samples was within 15% of the dose solution.

[0086] The toxicity of the test articles to the various cell lines in the study was assessed by measuring lactate dehydrogenase (LDH) released from the cells. Incubation medium not exposed to cells will serve as a background control. Incubation medium was collected from cells exposed to the no-test-article solvent control incubation medium (containing only the positive control substrate and inhibitor solvent, 0.2% v / v DMSO) (negative control), 1% Triton X-100 (positive control), solvent control (0 μM sample containing 0.2% v / v DMSO and test article solvent), and selected concentrations of test article. The toxicity observed with the test article was ≤25% compared to that of the positive control.

[0087] A stock solution (e.g., 10 mM) of radiolabeled transporter substrate was prepared in DMSO. 14 [C]-metformin (1 mM) was provided as a solid and prepared in Hank's Balanced Salt Solution (HBSS). Control inhibitors were prepared in DMSO (e.g., 10 mM). Substrate and control inhibitor or DMSO for solvent controls were spiked into the incubation medium at 0.1% v / v DMSO. Test articles were spiked into the incubation medium in the appropriate solvent, and the solvent concentration was adjusted to be the same for all incubations.

[0088] Nonspecific binding of the test article was evaluated to select incubation vessels free of cells. Test articles were mixed with the applicable incubation medium at low and high concentrations separately and incubated in 24-well cell culture plates in the absence of cells. After the incubation period, aliquots of the mixture were collected and analyzed by LC-MS / MS and compared with the dose solution (100% solution). A standard curve was included. Recovery was determined from the area ratio.

[0089] Before the experiment, cell culture plates (transporter-expressing and control cells) were removed from the incubator, the cell culture medium was removed, and 1 mL of incubation medium was added to the plate to rinse the cell culture medium from the cells. The incubation medium was replaced with incubation medium containing levocetconazole, a positive control inhibitor, or a solvent control (0.3 mL), and the plate was preincubated. After preincubation, the incubation medium was replaced with incubation medium containing levocetconazole, a positive control inhibitor, or a solvent control and the probe substrate. The samples were incubated for the indicated time. After incubation, the incubation medium was removed, and the cells were rinsed once with 1 mL of ice-cold phosphate-buffered saline (PBS) containing 0.2% w / v bovine serum albumin (BSA) and twice with ice-cold PBS. The PBS was removed, and 0.5 mL of 0.1 M sodium hydroxide was added. The cells were lysed and suspended by pipetting up and down. Aliquots of the medium were added to 96-well plates, diluted with scintillation fluid, and analyzed on a MicroBeta scintillation counter. The amount of protein in each incubation was determined by bicinchoninic acid assay.

[0090] Uptake of the relevant probe substrate in transporter-expressing and control cells in the presence and absence of known inhibitors served as positive controls. Transporter-specific uptake of the probe substrate or test article was determined by subtracting uptake in control cells from uptake in transporter-expressing cells. IC 50 Values ​​are determined from the reduction in activity (e.g., percent of control) when inhibition exceeds 50%, and are calculated as a 4-parameter IC 50 It was calculated by nonlinear regression using the equation: To calculate the recovery rate, samples were taken from the incubation medium at 0 min (dose solution) and at the final incubation time and calculated.

[0091] Transporter-expressing human embryonic kidney 293 (HEK293) cells transfected with vectors containing human transporter cDNAs for MATE1 and OCT2, and control cells (HEK293 cells transfected with vector alone) were used in experiments to evaluate levocetconazole as an inhibitor of MATE1 or OCT2.

[0092] HEK293 cells were cultured in cell culture flasks in Dulbecco's modified Eagle's medium (DMEM) supplemented with fetal bovine serum (FBS, 8.9% v / v), antibiotic / antimycotic (0.89% v / v), and L-glutamine (1.79 mM) in a humidified culture chamber (37 ± 1°C, 95 ± 5% relative humidity, and 5 ± 1% CO2). The medium was changed every 2–3 days, and cells were passaged when they reached confluence. HEPES (Sigma-Aldrich, Saint Louis) was the incubation medium for OCT2-expressing HEK293 cells. No cell loss was observed during incubation with OCT2-expressing HEK293 cells.

[0093] Caco-2 cells were cultured on a porous membrane in a transwell plate to form a confluent monolayer with tight junctions. The monolayer separates the apical and basolateral compartments of the transwell. Caco-2 cells were cultured in Eagle's minimal essential medium (EMEM) supplemented with FBS (8.9% v / v), non-essential amino acids (0.89% v / v), and penicillin-streptomycin (45 U / mL and 45 μg / mL, respectively) in a humidified culture chamber (37 ± 1°C, 95 ± 5% relative humidity, and 5 ± 1% CO2). The medium was changed every 2–3 days, and cells were passaged when they reached confluence.

[0094] MDCKII cells were cultured on a porous membrane in a transwell plate to form a confluent monolayer with tight junctions. The monolayer separates the apical and basolateral compartments of the transwell. MDCKII cells were cultured in DMEM supplemented with FBS (10% v / v) and penicillin-streptomycin (45 U / mL and 45 μg / mL, respectively) in a humidified culture chamber (37 ± 2°C, 95 ± 5% relative humidity, and 5 ± 1% CO2) in cell culture flasks. The medium was changed every 2–3 days, and cells were passaged when they reached confluence.

[0095] The table below shows the results of inhibition experiments using ketoconazole and levocetoconazole. Where applicable, n is the number of replicates, NA is not applicable, and SD refers to the standard deviation. Unless otherwise noted, values ​​are triplicate determinations rounded to three significant figures, and standard deviations are rounded to the same precision. Percentages are rounded to one decimal place, except for values ​​≥ 100, which are rounded to the nearest integer.

[0096] [Table 3]

[0097] [Table 4]

[0098] [Table 5]

[0099] [Table 6]

[0100] As can be seen from the table above, levocetanoconazole has an IC50 of 0.218 μM. 50 inhibits OCT, which is due to the use of racemic ketoconazole (IC 50= 1.52 μM).

[0101] Example 2 Phase I Study of Co-Administered Levocetconazole and Metformin This was a phase I, open-label, three-period, fixed-sequence study in 32 healthy male and female subjects (approximately 16 per sex) designed to evaluate the effect of levocetconazole on the pharmacokinetics of a single 500 mg dose of metformin. The study consisted of a 21-day screening period, a metformin-only treatment period (Period 1, Treatment A), a levocetconazole dose-escalation treatment period (Period 2) to achieve the dose level to be used in Period 3, and a metformin and levocetconazole coadministration treatment period (Period 3, Treatment B). Urine samples were also collected before dose administration and at specified intervals (0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours, and 36-48 hours post-dose) for 48 hours after dose administration to measure metformin recovery.

[0102] All subjects received a single oral dose of 500 mg metformin in Period 1.

[0103] Phase 2 was a dose-escalation period designed to gradually increase the levocetoconazole dose up to the 600 mg levocetoconazole dose level taken every 12 hours (Q12H) used in Phase 3. Phase 2 continued from Days 4 through 27 of the study. Subjects received 150 mg, 300 mg, 450 mg, and 600 mg levocetoconazole Q12H (approximate timing at home) for four consecutive weekly escalation cycles starting at Dose Level 1 on Day 4. For Dose Level 1, subjects received 150 mg Q12H. For Dose Levels 2 and 3, subjects received 300 mg and 450 mg levocetoconazole Q12H, respectively. For Dose Level 4, subjects received 600 mg levocetoconazole Q12H. Subjects received six doses of 600 mg levocetconazole alone prior to co-administration of levocetconazole and metformin in Period 3.

[0104] Period 3 was a drug-drug interaction evaluation period, in which levocetconazole 600 mg was coadministered with a single oral dose of 500 mg metformin on the morning of Day 28. Subjects received five repeated oral doses of 600 mg levocetconazole Q12H for a total daily dose of 1200 mg. Period 3 continued on Days 28 through 31 of the study. Again, urine was collected pre-dose and at specified intervals (0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours, and 36-48 hours post-dose) for 48 hours post-dose to measure metformin recovery.

[0105] Preliminary metformin pharmacokinetic parameters are listed in Table 5. There is an increase in Cmax and AUC and a decrease in Cl / F in the third period.

[0106] [Table 7]

[0107] Metformin coadministered with levocetconazole in Period 3 was compared with metformin alone in Period 1. The effect of levocetconazole on metformin pharmacokinetics is summarized in Table 6. Administration of levocetconazole increases metformin exposure by approximately twofold.

[0108] [Table 8]

[0109] A comparison of urinary pharmacokinetic parameters was performed between metformin co-administered with levocetconazole in Period 3 and metformin alone in Period 1. The results are shown in Table 7.

[0110] [Table 9]

[0111] Plasma data and additional pharmacokinetic parameters from plasma support a drug-drug interaction between levocetconazole and metformin via a mechanism of reduced systemic clearance of metformin. Additional urinary data support an effect of levocetconazole in reducing the urinary clearance of metformin. Metformin is not metabolized and is excreted unchanged primarily, but not exclusively, in the urine.

[0112] These previously undescribed effects of levocetoconazole to inhibit OCT2 in vitro, coupled with the novel effects of drug coadministration on metformin's renal and systemic clearance and urinary excretion, and the magnitude of the increase in metformin AUC / Cmax resulting from the inhibition of clearance, are unexpected and clinically significant.

[0113] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein and / or listed in the Application Data Sheets are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to provide further embodiments using concepts from the various patents, applications, and publications.

[0114] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. 1. A pharmaceutical composition for the treatment of hypercortisolism in a subject with Cushing's syndrome, comprising: levocetconazole, or a pharmaceutically acceptable salt thereof, administered in a therapeutically effective amount to said subject in need thereof; the pharmaceutical composition is co-administered with a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof; the subject also has type 2 diabetes and has had previous surgery or radiation to treat Cushing's syndrome in the subject; wherein the therapeutically effective amount of the pharmaceutical composition is determined via a titration scheme comprising escalating doses of the pharmaceutical composition; The metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose reduced from the therapeutically effective amount if the subject experiences a dose limiting event, wherein the dose limiting event is reduced fasting blood glucose levels, abnormal renal function, low vitamin B-12 levels, or any combination thereof.

2. 1. A pharmaceutical composition for the treatment of hypercortisolism in a subject with Cushing's syndrome, comprising: levocetconazole, or a pharmaceutically acceptable salt thereof, administered to said subject in need thereof in a therapeutically effective amount; the pharmaceutical composition is co-administered with a therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof; the subject also has type 2 diabetes, and the subject has not had surgery or radiation to treat Cushing's syndrome; wherein the therapeutically effective amount of the pharmaceutical composition is determined via a titration scheme comprising escalating doses of the pharmaceutical composition; The metformin, or a pharmaceutically acceptable salt thereof, is administered at a dose reduced from the therapeutically effective amount if the subject experiences a dose limiting event, wherein the dose limiting event is reduced fasting blood glucose levels, abnormal renal function, low vitamin B-12 levels, or any combination thereof.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is administered in the therapeutically effective amount after administration of metformin or a pharmaceutically acceptable salt thereof to the subject.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is administered in the therapeutically effective amount prior to administration of the metformin or pharmaceutically acceptable salt thereof to the subject.

5. 5. The pharmaceutical composition of claim 4, wherein the metformin or a pharmaceutically acceptable salt thereof is administered at a starting dose that is lower than the amount that would be administered to a subject not receiving the pharmaceutical composition.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein said administration of said pharmaceutical composition increases systemic exposure to metformin or a pharmaceutically acceptable salt thereof.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 25%.

8. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the therapeutically effective amount of metformin, or a pharmaceutically acceptable salt thereof, is reduced by at least 50%.

9. The pharmaceutical composition according to any one of claims 1 to 6, which reduces the administration frequency of metformin or a pharmaceutically acceptable salt thereof.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered in a titration scheme involving dose escalation until one or more of the following conditions are met: (1) the subject has a sufficient response; (2) the highest labeled-specified dose is reached; or (3) a dose-limiting event occurs.

11. The titration scheme comprises: (i) administering a first dose of levocetconazole, or a pharmaceutically acceptable salt thereof, for a first period of time; (ii) increasing the dose in increments of 150 mg per day; (iii) determining whether the subject tolerates the increased dose; Including, (i) to (iii) are repeated as long as the subject tolerates the increased dose; 11. The pharmaceutical composition of any one of claims 1 to 10, wherein if the subject does not tolerate the increased dose, the patient's dose is equal to the difference between the further increased dose and the increment value for the final (i) to (iii) iterations.

12. 12. The pharmaceutical composition of claim 11, wherein the first dose of the pharmaceutical composition is 150 mg administered twice daily.

13. The pharmaceutical composition according to any one of claims 1 to 10, wherein the therapeutically effective amount of the pharmaceutical composition is 150 mg to 1200 mg per day.

14. The pharmaceutical composition of any one of claims 1 to 10, wherein the therapeutically effective amount of the pharmaceutical composition is 600 mg twice daily.

15. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein co-administration of the pharmaceutical composition and metformin, or a pharmaceutically acceptable salt thereof, may result in one or more exposure-related adverse reactions associated with administration of metformin, or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the levocetconazole or a pharmaceutically acceptable salt thereof is in a dosage form suitable for oral administration.

17. 17. The pharmaceutical composition of claim 16, wherein the dosage form is an immediate release tablet.

18. 18. The pharmaceutical composition of claim 17, wherein the tablet comprises one or more pharmaceutical excipients selected from microcrystalline cellulose, lactose, corn starch, colloidal silicon dioxide, and magnesium stearate.

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