Treatment methods for diseases treated with levocetoconazole

Abstract

This invention provides a pharmaceutical composition for use in methods of treating diseases with levocetoconazole. [Solution] A pharmaceutical composition is provided for use in a method for treating persistent or relapsing Cushing's syndrome, wherein the subject is co-administered with a multidrug toxin efflux transporter 1 (MATE1) substrate or a pharmaceutically acceptable salt thereof, the method comprising: administering to the subject a therapeutically effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof, the therapeutically effective dose being determined via a dose-setting scheme; and in the dose-setting scheme for levocetoconazole, monitoring the subject for dose-limiting events, the dose-limiting events being due to increased exposure to the MATE1 substrate, and reducing the dose of the MATE1 substrate or a pharmaceutically acceptable salt thereof administered to the subject if the subject experiences a dose-limiting event.

Description

[Technical Field]

[0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 62 / 813,399, filed March 4, 2019, whose entire disclosure is incorporated by reference for its entire purpose. [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, excessive secretion of adrenocorticotropic hormone (ACTH) leads to Cushing's syndrome, most commonly via a pituitary corticotropin adenoma, less frequently via an extrapituitary tumor (ectopic ACTH syndrome), or, in rare cases, via 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 unilateral adrenal cortical tumors, 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®, containing ketoconazole, is registered in several countries outside the United States for the treatment of Cushing's syndrome. Ketoconazole reduces or inhibits adrenal steroid production by inhibiting several adrenal steroid-producing 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 included in large prospective clinical trials, but has been included in several small open-label trials and larger retrospective case series. Ketoconazole has been reported to normalize cortisol excess 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 hepatotoxicity. High levels of transaminase are common. Ketoconazole also has significant potential drug interactions, including strong inhibition of drug-metabolizing enzymes, including CYP3A4, which increases the risk of QT prolongation. Despite the availability of two FDA-approved drugs, ketoconazole continues to be a common off-label use in the United States to treat Cushing's syndrome and appears to be the most frequently prescribed medical therapy for Cushing's syndrome, reflecting a persistent need not addressed by approved treatments.

[0005] Levocetoconazole (Recorlev®, COR-003, 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(IH-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl]piperazine) is a cortisol synthesis inhibitor in clinical trials. Levocetoconazole is the 2S,4R enantiomer of ketoconazole. Nonclinical and clinical data suggest that levocetoconazole inhibits cortisol synthesis more strongly and reaches higher plasma concentrations after ketoconazole administration compared to the 2R,4S enantiomer of ketoconazole. [Overview of the project] [Means for solving the problem]

[0006] A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, the subject also receiving a therapeutically effective dose of a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. The therapeutically effective dose of the MATE1 substrate or OCT2 substrate is reduced compared to subjects who have not received levocetoconazole or a pharmaceutically acceptable salt thereof.

[0007] Treatment methods are also provided for diseases selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancers in subjects requiring treatment, wherein subjects are co-administered a therapeutically effective dose of multidrug / toxin efflux transporter 1 (MATE1) substrate or organic cation transporter 2 (OCT2) substrate, and the method is as follows: To reduce the amount of MATE1 substrate or OCT2 substrate administered to the subject, Next, administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is initiated, The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

[0008] In some embodiments, reducing the amount of MATE1 substrate or OCT2 substrate being administered to a subject includes discontinuing the administration of MATE1 substrate or OCT2 substrate.

[0009] Furthermore, a method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, the subject also receiving a therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. The therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof, is reduced compared to subjects who have not received levocetoconazole, or a pharmaceutically acceptable salt thereof.

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

[0011] Treatment methods are also provided for patients requiring treatment for diseases selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancers, in which patients are co-administered a therapeutically effective dose of metformin, and the method is: To reduce the amount of metformin being administered to the subject, Next, administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is initiated, The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

[0012] Furthermore, methods for treating diseases selected from Cushing's disease, syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer are provided, the methods of which are: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. Next, the patient decides to initiate treatment with a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or OCT2 substrate is administered in a smaller dose than would be administered to a patient not receiving levocetoconazole or a pharmaceutically acceptable salt thereof.

[0013] Furthermore, a method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. Next, the patient decides to initiate treatment with metformin, the amount of metformin to be administered is less than the amount that would be administered to a patient who has not been administered levocetoconazole 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 levocetoconazole or a pharmaceutically acceptable salt thereof. In some embodiments, the starting dose is increased by an increment (e.g., 250 mg) less than the amount that would be used in a patient not receiving levocetoconazole or a pharmaceutically acceptable salt thereof (e.g., 500 mg).

[0015] Also provided is a method of treating a disease selected from Cushing's disease, Cushing's syndrome, cyclic Cushing's syndrome, exogenous Cushing's syndrome, Cushing's syndrome, hyperglycemia, multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject that requires treatment, the subject is also administered metformin, and the method comprises: administering to a subject that needs it a therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, the therapeutically effective amount of levoketoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dosing scheme, administration of levoketoconazole, or a pharmaceutically acceptable salt thereof, increases the systemic exposure to metformin by about two-fold.

[0016] These and other aspects of the invention will become apparent with reference to the following detailed description. For this purpose, various references are set forth herein that describe in more detail certain background information, procedures, compounds, and / or compositions, each of which is incorporated herein by reference in its entirety.

Mode for Carrying Out the Invention

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

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

[0019] When a range of values is disclosed and the notation "n1...~n2" or "between n1 and n2" is used (where n1 and n2 are numbers), unless otherwise specified, this notation is intended to include the numbers themselves and the numbers within the range between them. This range can be an integer or can be 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 in integer units. As an example, consider the range "1 to 3 μM (micromolar)" which is intended to include any number of significant figures from 1 μM, 3 μM, and all those in between (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0020] The term "about" modifies the numerical value it precedes and indicates such a value as a variable within an allowable error. When no allowable error, such as the standard deviation with respect to an average value given in a data chart or table, is cited, the term "about" means a range that encompasses the cited value and the ranges included by rounding up or down that value, taking into account significant figures.

[0021] Any definition in this specification can be used in combination with any other definition for describing a composite structural group. Conventionally, the last element of any such definition is what attaches to the parent moiety. For example, the composite group alkylamide 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] As used herein, the term “disease” is generally synonymous with and intended to be used interchangeably with the terms “disorder,” “syndrome,” and “condition” (as in medical conditions) (all of which reflect one abnormal condition in which the normal function of a human or animal body or part thereof is impaired, typically manifested by distinguishing signs and symptoms, and which reduces the lifespan or quality of life of the human or animal).

[0023] The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described herein. Such administration includes substantially simultaneous co-administration of these therapeutic agents, for example, in a single capsule having a fixed ratio of active ingredients, or in a number of separate capsules for each active ingredient. In addition, such administration also includes the sequential use of each type of therapeutic agent. In any case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or disorder described herein.

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

[0025] The term "therapeutably tolerable" refers to compounds that are suitable for use in contact with patient tissues without excessive toxicity, irritation, and allergic reactions, that meet an ideal benefit / risk ratio, and that are effective for their intended use.

[0026] As used herein, the reference to “treatment” of a patient is intended to include prevention. Treatment can also be preventive, that is, it can include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of prevention of infection by a pathogen, or it may include prevention of disease progression. For example, prevention of disease may not mean the complete elimination of any effect at any level associated with the disease, but may mean the prevention of symptoms of the disease up to a clinically significant or detectable level. Prevention of disease may also mean preventing the progression of the disease up to a later stage. In certain embodiments, prevention of disease may include the prevention of intermittent seizures and the prevention of permanent muscle weakness, such as irreversible conditions of functional impairment resulting from 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 human.

[0028] As used herein, a patient is said to be “tolerant” of a dose of a compound if administration of that dose to the patient does not result in an unacceptable adverse event or an unacceptable combination of adverse events. Those skilled in the art will recognize that tolerance is a subjective measure, and what is tolerable in one patient may not be tolerable in another. For example, one patient may not be tolerant of a headache, while a second patient may be tolerant of a headache but not of vomiting, while a third patient may be tolerant of either a headache alone or vomiting alone, but not of a combination of headache and vomiting, even if the severity of each is less severe than when experienced individually.

[0029] As used herein, “adverse event” refers to an undesirable medical occurrence related to the treatment of a drug.

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

[0031] As used herein, “updosing” of a compound refers to increasing the amount of the compound to achieve a therapeutic effect that occurs before the patient reaches dose-limiting intolerance. Updosing may be achieved with one or more dose increments, which may be the same or different.

[0032] The compounds disclosed herein may exist as therapeutically acceptable salts. This 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 generally be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts may be useful in the preparation and purification of the compounds in question. Base addition salts may also be formed and may be pharmaceutically acceptable.

[0033] The term “therapeutably acceptable salt,” as used herein, refers to a salt or zwitterionic form of a compound disclosed herein, which is water-soluble, oil-soluble, or dispersible, and is therapeutically acceptable as defined herein. Salts may be prepared during the final isolation and purification of the compound, or separately by reacting a suitable compound in its free base form with a suitable acid. Typical acid addition salts include acetate, adipine, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisinate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, and malonate. This includes salts, DL-mandelates, mesitylene sulfonates, methanesulfonates, naphthylene sulfonates, nicotinates, 2-naphthalene sulfonates, oxalates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphonates, picrinates, pivalates, propions, pyroglutamates, succinates, sulfonates, tartrates, L-tartrates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfonates (p-tosylates), and undecanoates. The basic groups of the compounds disclosed herein can also be quaternized with 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, as well as organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordinating compounds with alkali metal or alkaline earth ions. Accordingly, this disclosure intends to include sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0034] Base addition salts can be prepared during the final isolation and purification of compounds by reacting the carboxyl group with a suitable base such as a metal cation hydroxide, carbonate, or bicarbonate, or ammonia or an organic primary, secondary, or tertiary amine. Cationic salts that are therapeutically acceptable 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 forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0035] Salts of compounds can be prepared by reacting a suitable compound in its free base form with a suitable acid.

[0036] Metformin refers to N,N-dimethylimidodicarbonimidodiamide hydrochloride. Metformin formulations have been previously reported under the FDA-approved drug label GLUCOPHAGE as a diet and exercise adjunct 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 are 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 are 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 750mg tablets contain the inactive ingredients hypromellose, sodium carboxymethylcellulose, magnesium stearate, and red iron oxide pigment.

[0038] The standard dosage for metformin is: Adult dosage for GLUCOPHAGE: • Starting dose: 500 mg orally twice daily or 850 mg once daily with meals • Administer in divided doses, increasing the dose by 500 mg weekly or 850 mg every two weeks, up to a maximum dose of 2550 mg / day. • Doses exceeding 2000 mg may be more tolerable if administered three times a day with meals. Adult dosage of GLUCOPHAGE XR: • Starting dose: 500 mg orally once daily with dinner Take with dinner, increasing the dose by 500 mg weekly, up to a maximum of 2000 mg once daily. Patients receiving GLUCOPHAGE may switch to GLUCOPHAGE XR once daily, up to 2000 mg once daily, for the same total daily dose. GLUCOPHAGE dosage for children: • Starting dose: 500 mg orally twice daily with meals • Administer in divided doses twice daily, increasing the dosage by 500 mg per week up to a maximum of 2000 mg / day.

[0039] An oral solution of metformin is also approved. It contains 500 mg of metformin hydrochloride per 5 mL, along with the following inactive ingredients: saccharin calcium, 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 (10-16 years old).

[0040] A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, the subject also receiving a therapeutically effective dose of a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. The therapeutically effective dose of the MATE1 substrate or OCT2 substrate is reduced compared to subjects who have not received levocetoconazole or a pharmaceutically acceptable salt thereof.

[0041] Treatment methods are also provided for diseases selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancers in subjects requiring treatment, wherein subjects are co-administered a therapeutically effective dose of multidrug / toxin efflux transporter 1 (MATE1) substrate or organic cation transporter 2 (OCT2) substrate, and the method is as follows: To reduce the amount of MATE1 substrate or OCT2 substrate administered to the subject, Next, administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is initiated, The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

[0042] In some embodiments, reducing the amount of MATE1 substrate or OCT2 substrate being administered to a subject includes discontinuing the administration of MATE1 substrate or OCT2 substrate.

[0043] Furthermore, a method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, the subject also receiving a therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. The therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof, is reduced compared to subjects who have not received levocetoconazole, or a pharmaceutically acceptable salt thereof.

[0044] Treatment methods are also provided for patients requiring treatment for diseases selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancers, in which patients are co-administered a therapeutically effective dose of metformin, and the method is: To reduce the amount of metformin being administered to the subject, Next, administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is initiated, The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

[0045] Furthermore, a method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. Next, the patient decides to initiate treatment with a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or OCT2 substrate is administered in a smaller dose than would be administered to a patient not receiving levocetoconazole or a pharmaceutically acceptable salt thereof.

[0046] Furthermore, methods for treating diseases selected from Cushing's disease, syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer are provided, the methods of which are: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. Next, the patient decides to initiate treatment with a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or OCT2 substrate is administered in a starting dose lower than that which would be administered to a patient not receiving levocetoconazole or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the method further includes increasing the starting dose by an amount less than the amount that would be administered to a patient who has not been administered levocetoconazole or a pharmaceutically acceptable salt thereof. In some embodiments, the method further includes increasing the starting dose by 250 mg increments compared to a 500 mg increment that would be administered to a patient who has not been administered levocetoconazole or a pharmaceutically acceptable salt thereof.

[0048] Furthermore, a method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer is provided, the method being: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. Next, the patient decides to initiate treatment with metformin, the amount of metformin to be administered is less than the amount that would be administered to a patient who has not been administered levocetoconazole or a pharmaceutically acceptable salt thereof.

[0049] Treatment methods are also provided for patients requiring treatment for diseases selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancers, in which patients are also administered metformin: This includes administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need. The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. Administration of levocetoconazole or a pharmaceutically acceptable salt thereof increases systemic exposure to metformin by approximately twofold.

[0050] In certain embodiments, the disease is Cushing's syndrome. In certain embodiments, the disease is periodic Cushing's syndrome. In certain embodiments, the disease is persistent or recurrent Cushing's syndrome. In certain embodiments, the subject has prior surgery or radiation to treat the subject's Cushing's syndrome. In certain embodiments, the subject does not have prior surgery or radiation to treat the subject's Cushing's syndrome. In certain embodiments, the disease is Cushing's disease.

[0051] In certain embodiments, the disease is exogenous cortisol excess. In certain embodiments, the disease is cortisol excess. In certain embodiments, the disease is hyperglycemia. In certain embodiments, the disease is multiple endocrine neoplasia type 1. In certain embodiments, the disease is McKoon-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 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 sensitive to estrogen or progesterone.

[0053] In certain embodiments, the disease is impaired susceptibility to treatment with levocetoconazole or a pharmaceutically acceptable salt thereof.

[0054] In certain embodiments, the dose setting scheme includes updosing levocetoconazole, or a pharmaceutically acceptable salt thereof, until one or more of the following conditions are met: (1) the subject has a sufficient response; (2) the maximum designated dose is reached; or (3) a dose-limiting event occurs.

[0055] In certain embodiments, the dose-setting scheme includes: administering a first dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, for a first period, e.g., about one week; increasing the dose by an amount equal to an increment; and determining whether the subject tolerates the increased dose; repeating this cycle as long as the subject tolerates the increased dose, with the increment being the same or different in each cycle repeat; and if the subject does not tolerate the increased dose, the patient's dose is equal to the difference between a further increased dose and the increment for the final cycle repeat. In certain embodiments, the initial dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is 150 mg twice daily. In certain embodiments, the increment 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 therapeutic effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg to 1200 mg / day. In certain embodiments, the therapeutic effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg once daily. In certain embodiments, the therapeutic effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg twice daily. In certain embodiments, the therapeutic effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 300 mg twice daily. In certain embodiments, the therapeutic effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 450 mg twice daily. In certain embodiments, the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is 600 mg twice daily.

[0057] In certain embodiments, the dose-setting scheme includes an initial dose reduction. In certain embodiments, the initial dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is 150 mg twice daily, and the dose reduction 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 dose-setting scheme described herein. In certain embodiments, the administration is maintained at 150 mg daily.

[0058] In certain embodiments, the dose-setting scheme includes updosing levocetoconazole, 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 measurement) or late-night salivary cortisol (LNSC) or multiply-sampled serum cortisol (MSSC). In certain embodiments, normalization of UFC, LNSC, or MSSC includes a decrease of at least 50% of the mean UFC. In certain embodiments, a sufficient response is a decrease of less than 50% from the baseline cortisol level. In certain embodiments, updosing of levocetoconazole is continued until at least two of the cortisol measurements selected from UFC, LNSC, and MSSC are below the baseline cortisol level, for example, by at least 50% from the baseline cortisol level. In certain embodiments, the updo setting of levoketoconazole is stopped when UFC, LNSC and MSSC normalize or fall below baseline cortisol levels. In certain embodiments, a sufficient response includes improvement in cortisol hypertension as measured, for example, via hair cortisol or multiple-collected sweat cortisol.

[0059] In certain embodiments, the dose-setting scheme further includes a maintenance phase in which the subject is administered a therapeutically effective dose of levocetoconazole at a fixed dose.

[0060] In certain embodiments, the dose setting scheme includes updosing levocetoconazole or a pharmaceutically acceptable salt thereof until the subject experiences a dose-limiting event. In certain embodiments, the method further includes reducing the dose of levocetoconazole or a pharmaceutically acceptable salt thereof after the subject has experienced a dose-limiting event. In certain embodiments, the method further includes temporarily suspending administration of levocetoconazole or a pharmaceutically acceptable salt thereof after the subject has experienced 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 is due to increased exposure to the MATE1 substrate or the OCT2 substrate. In certain embodiments, the method further includes informing the subject or healthcare worker that co-administration of levocetoconazole, or a pharmaceutically acceptable salt thereof, and the MATE1 substrate or the OCT2 substrate may result in increased exposure to the MATE1 substrate or the OCT2 substrate. In certain embodiments, the method further includes informing the subject or healthcare worker that co-administration of levocetoconazole, or a pharmaceutically acceptable salt thereof, and the MATE1 substrate or the OCT2 substrate may result in one or more exposure-related adverse reactions associated with the administration of the MATE1 substrate or the 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 the administration of the MATE1 substrate or the OCT2 substrate.

[0062] In certain embodiments, dose-limiting events are due to increased exposure to metformin. In certain embodiments, the method further includes informing the subject or healthcare worker that co-administration of levocetoconazole, 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 informing the subject or healthcare worker that co-administration of levocetoconazole, 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 serum concentrations 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 selecting one or more exposure-related adverse reactions from diarrhea, nausea / vomiting, flatulence, asthenia, indigestion, abdominal discomfort, lactic acidosis, and headache.

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

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

[0065] In certain embodiments, the dose-limiting event is an elevated liver function test (LFT). In certain embodiments, LFT includes tests that analyze 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 whole). In certain embodiments, the elevated LFT is at least 1.5 times the upper limit of normal in the reference range. In certain embodiments, the elevated LFT is at least 2 times the upper limit of normal in the reference range. In certain embodiments, the elevation further includes an elevation of more than 1 times the upper limit of normal in either ALT or AST. In that sense, the normal range for a given analyte may vary depending on the test 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 type B lactic aldosis. In certain embodiments, the dose-limiting event is a blood pH of less than 7.35 and a lactate concentration greater than 5 mmol / L. In some embodiments, the subjects also have a reduced serum bicarbonate concentration (e.g., less than 22 mmol / L) and / or an anion gap greater than 12 meQ / L.

[0067] In certain embodiments, the dose-limiting event is abnormal renal function. In certain embodiments, the method further includes monitoring eGFR. In certain embodiments, abnormal renal function is 30 mL / min / 1.73 m 2 Includes an estimated glomerular filtration rate (eGFR) of less than 30–45 mL / min / 1.73m². In certain embodiments, abnormal renal function is 30–45 mL / min / 1.73m². 2 This includes eGFR. In a particular embodiment, eGFR is 35 mL / min / 1.73 m 2 If the level falls below this, the method further includes discontinuing the administration of metformin.

[0068] In certain embodiments, the dose-limiting event is a decrease in fasting glucose levels. In 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 levels.

[0070] In certain embodiments, the MATE1 substrate is selected from the following substrates (or pharmaceutically acceptable salts thereof):

[0071] [Table 1]

[0072] In certain embodiments, the MATE1 substrate is selected from cimetidine, abemaciclib, levofloxacin, ciprofloxacin, topotecan, metformin, cephalexin, acyclovir, cefradin, 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 following substrates (or pharmaceutically acceptable salts 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 pharmaceutically acceptable salts 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%, 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 frequency of administration of the MATE1 substrate or OCT2 substrate is reduced. For example, if the dose is not reduced, the frequency of administration may 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 frequency of administration of metformin or a pharmaceutically acceptable salt thereof is reduced. For example, if the dose is not reduced, the frequency of administration may be extended from twice daily (BID) to once daily (QD), or every other day (QOD), etc.

[0078] The disclosed compounds may be administered as raw chemical substances, but they may also exist as pharmaceutical formulations. Accordingly, pharmaceutical formulations are provided herein that include 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 components. The carriers must be “acceptable” in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient. The appropriate formulation depends on the chosen route of administration. Any of the well-known techniques, carriers, and excipients may 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, dissolution, granulation, sugar-coated tablet formation, micronization, emulsification, encapsulation, encapsulation, or compression processes.

[0079] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including transdermal, buccal, sublingual, and intraocular) administration, but the most appropriate route may depend, for example, on the recipient's condition and impairment. The formulations may conveniently exist in unit dosage forms and may be prepared by any method well known in the field of pharmacy. Typically, these methods involve the step of conjugating the compound disclosed herein, or a pharmaceutically acceptable salt thereof ("active ingredient"), to a carrier consisting of one or more accessory components. Generally, the formulations are prepared by uniformly and closely conjugating the active ingredient to a liquid carrier or a pulverized solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0080] Pharmaceutical formulations that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealable capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, sometimes with one or more adjuncts. Compressed tablets may be prepared by compressing a free-flowing active ingredient, such as a powder or granules, mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent, in a suitable machine. Tablets may be coated or grooved, and may be formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration must be in a dosage appropriate for such administration. Push-in 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 oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Sugar-coated tablet cores are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and an optional organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of doses of the active compound.

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

[0082] The compound may be administered orally or by injection at doses ranging from 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 forms of presentation, provided in individual units, conveniently contain the amount of one or more compounds effective at such doses, 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 skilled in the art in using the present disclosure. The examples do not limit the scope of the present disclosure in any way. [Examples]

[0084] Example 1: Drug-drug interaction study using MATE1 and OCT2 substrates This study was designed to evaluate levocetoconazole as an inhibitor of MATE1 or OCT2. Compounds that are substrates or inhibitors of transporters can be victims or perpetrators of drug-drug interactions. Experiments were conducted as described in the FDA and EMA guidance document drafts, Drug Interaction Studies (FDA 2017, EMA 2013). Probe substrates were [ 14 [C] It was metformin.

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

[0086] The toxicity of the test substance to various cell lines in the study was evaluated by measuring lactate dehydrogenase (LDH) released from cells. Incubation media not exposed to cells would serve as a background control. Incubation media were collected from cells exposed to unexposed solvent-controlled incubation media (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 substance solvent), and selected concentrations of the test substance. The toxicity observed with the test substance was ≤25% compared to that of the positive control.

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

[0088] Nonspecific binding of the test substance was evaluated to select incubation vessels in which cells were absent. The test substance was mixed separately with applicable incubation media at low and high concentrations and incubated in 24-well cell culture plates, but no cells were present. After the incubation period, aliquots of the mixture were collected and analyzed by LC-MS / MS and compared to the dose solution (100% solution). A standard curve was included. Recovery rates were determined from the area ratio.

[0089] Before the experiment, the cell culture plates (transporter expression and control cells) were removed from the incubator, the cell culture medium was removed, and incubation medium (1 mL) was added to the plates to rinse the cells out of the cell culture medium. The incubation medium was replaced with incubation medium containing levoketoconazole, a positive control inhibitor, or a solvent control (0.3 mL), and the plates were pre-incubated. After pre-incubation, the incubation medium was replaced with incubation medium containing levoketoconazole, a positive control inhibitor, or a solvent control and probe substrate. The samples were incubated for the specified 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-specific antigen (BSA), and twice with ice-cold PBS. The PBS was removed, 0.5 mL of sodium hydroxide (0.1 M) was added, and the cells were lysed and suspended by pipetting up and down. Aliquots of the culture medium were added to a 96-well plate, diluted with scintillation solution, and analyzed on a MicroBeta scintillation counter. The amount of protein in each incubation was determined by bicinchoninic acid analysis.

[0090] The uptake of the relevant probe substrate in transporter-expressing cells and control cells, both in the presence and absence of known inhibitors, was positive control. Transporter-specific uptake of the probe substrate or test product was determined by subtracting uptake in control cells from uptake in transporter-expressing cells. IC 50 The value is determined from the decrease in activity (e.g., percentage of control) when inhibition exceeds 50%, and the 4-parameter IC50 is used. 50 The calculation was performed using nonlinear regression with an equation. To calculate the recovery rate, samples were taken from the incubation medium at 0 minutes (dose solution) and at the final incubation time, and the calculation was performed.

[0091] Levocetoconazole as an inhibitor of MATE1 or OCT2 was evaluated using human embryonic kidney 293 (HEK293) cells expressing the transporters, transfected with vectors containing human transporter cDNA for MATE1 and OCT2, and control cells (HEK293 cells transfected with only the vector).

[0092] HEK293 cells were cultured in cell culture flasks in a humidified culture chamber (37±1°C, 95±5% relative humidity, and 5±1% CO2) in Dulbecco's modified Eagle medium (DMEM) supplemented with fetal bovine serum (FBS, 8.9% v / v), antibiotics / antifungal agents (0.89% v / v), and L-glutamine (1.79 mM). The medium was changed every 2-3 days, and the cells were subcultured when they reached confluence. HEPES (Sigma-Aldrich, Saint Louis) was used as 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 separated the apical and basal outer compartments of the Transwell. Caco-2 cells were cultured in Eagle's minimal basal 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 the cells were subcultured 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 cell culture flasks in a humidified culture chamber (37 ± 2 °C, 95 ± 5% relative humidity, and 5 ± 1% CO2) in DMEM supplemented with FBS (10% v / v) and penicillin-streptomycin (45 U / mL and 45 μg / mL, respectively). The medium was changed every 2 - 3 days and the cells were passaged when they reached confluence.

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

[0096] [Table 3]

[0097] [Table 4]

[0098] [Table 5]

[0099] [Table 6]

[0100] As can be seen from the above table, levoketoconazole inhibits OCT at an IC 50 of 0.218 μM, which is lower than that of racemic ketoconazole (IC 50It was more potent than (=1.52 μM).

[0101] Example 2 Phase I study of co-administration of levocetoconazole and metformin This was a Phase I, open-label, three-stage, fixed-dosing-sequence study in 32 healthy men and women (approximately 16 per sex) designed to evaluate the effect of levocetoconazole on the pharmacokinetics of a single 500 mg dose of metformin. The study consisted of a screening period up to 21 days, a metformin-only treatment period (Stage 1, Treatment A), a levocetoconazole dose-increasing treatment period to achieve the dose level to be used in Stage 3 (Stage 2), and a co-administration treatment period of metformin and levocetoconazole (Stage 3, Treatment B). Urine samples were 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-administration) and 48 hours post-administration to measure metformin recovery.

[0102] All subjects received a single oral dose of 500 mg of metformin during the first phase.

[0103] Phase 2 was a dose escalation period designed to gradually increase the levocetoconazole dose up to a dose level of 600 mg of levocetoconazole taken every 12 hours (Q12H), which was used in Phase 3. Phase 2 continued from days 4 to 27 of the study. Participants received 150 mg, 300 mg, 450 mg, and 600 mg of levocetoconazole Q12H (at approximate timing at home) as four consecutive weekly escalation cycles starting at dose level 1 on day 4. At dose level 1, participants received 150 mg Q12H. At dose levels 2 and 3, participants received 300 mg and 450 mg of levocetoconazole Q12H, respectively. At dose level 4, participants received 600 mg of levocetoconazole Q12H. The subjects received six doses of 600 mg levocetoconazole monotherapy prior to co-administration of levocetoconazole and metformin in the third phase of treatment.

[0104] Phase 3 was the drug-drug interaction evaluation period, during which levocetoconazole 600 mg was co-administered with a single oral dose of 500 mg of metformin on the morning of day 28. The subjects received five repeated oral doses of 600 mg of levocetoconazole Q12H, for a total daily dose of 1200 mg. Phase 3 continued from day 28 to 31 of the study. Again, urine was collected before dose administration and at specified intervals (0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours, and 36-48 hours after dose administration) and 48 hours after dose administration to measure the recovery rate of metformin.

[0105] The preliminary metformin pharmacokinetic parameters are listed in Table 5. There is an increase in Cmax and AUC, and a decrease in Cl / F during the third phase.

[0106] [Table 7]

[0107] A comparison was made between metformin co-administered with levocetoconazole in Phase 3 and metformin monotherapy in Phase 1. Table 6 summarizes the effect of levocetoconazole on the pharmacokinetics of metformin. Levocetoconazole administration approximately doubled exposure to metformin.

[0108] [Table 8]

[0109] We compared the urinary pharmacokinetic parameters of metformin co-administered with levocetoconazole in the third phase with those of metformin alone in the first phase. The results are shown in Table 7.

[0110] [Table 9]

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

[0112] These previously unexplained effects of levocetoconazole, which inhibits OCT2 in vitro, are unpredictable and clinically significant, coupled with the novel effects of co-administration of the drug on metformin's renal and systemic clearance and urinary excretion, as well as the magnitude of the increase in metformin AUC / Cmax resulting from the inhibition of clearance.

[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 datasheet are incorporated herein by reference in their entirety. The aspects of the embodiments can be modified as necessary to provide further embodiments using various patent, application, and publication concepts.

[0114] These and other modifications can be made to the embodiments in light of the detailed description above. In general, the terms used in the following claims should not be interpreted as limiting the claims to the specific embodiments disclosed in the specification and claims, but rather as encompassing all possible embodiments along with the entire scope of equivalent rights granted to such claims. Accordingly, the claims are not limited by this disclosure.

Claims

1. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, wherein the subject is also co-administered a therapeutically effective dose of a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. A method wherein the therapeutically effective dose of the MATE1 substrate or OCT2 substrate is reduced compared to a subject who has not been administered levocetoconazole or a pharmaceutically acceptable salt thereof.

2. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject requiring treatment, wherein the subject is co-administered a therapeutically effective amount of multidrug / toxin efflux transporter 1 (MATE1) substrate or organic cation transporter 2 (OCT2) substrate, and the method is: To reduce the amount of MATE1 substrate or OCT2 substrate administered to the subject, This then includes initiating administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, A method by which the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

3. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: This involves administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need, wherein the subject is also co-administered a therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof; The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. A method wherein the therapeutically effective dose of metformin, or a pharmaceutically acceptable salt thereof, is reduced compared to a subject who has not been administered levocetoconazole, or a pharmaceutically acceptable salt thereof.

4. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject requiring treatment, wherein the subject is co-administered a therapeutically effective dose of metformin, and the method is: To reduce the amount of metformin administered to the aforementioned subjects, This then includes initiating administration of a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, A method by which the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme.

5. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, wherein the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. A method comprising: determining that the patient shall initiate treatment with a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or OCT2 substrate shall be administered in a smaller amount than that which would be administered to a patient not administered levocetoconazole or a pharmaceutically acceptable salt thereof.

6. A method for treating a disease selected from Cushing's disease, syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, wherein the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. A method comprising: determining that the patient will initiate treatment with a multidrug / toxin efflux transporter 1 (MATE1) substrate or an organic cation transporter 2 (OCT2) substrate, wherein the MATE1 substrate or OCT2 substrate will be administered in a starting dose less than that which would be administered to a patient not administered levocetoconazole or a pharmaceutically acceptable salt thereof.

7. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, wherein the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. A method comprising: then deciding that the patient shall initiate metformin treatment, wherein the metformin shall be administered in a smaller dose than that which would be administered to a patient not administered levocetoconazole or a pharmaceutically acceptable salt thereof.

8. A method for treating a disease selected from Cushing's disease, syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer: The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is administered to a subject in need, wherein the therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined through a dose-setting scheme. A method comprising: the patient deciding to initiate treatment with metformin, wherein the metformin is administered in a starting dose less than the amount that would be administered to a patient who has not been administered levocetoconazole or a pharmaceutically acceptable salt thereof.

9. A method for treating a disease selected from Cushing's disease, Cushing's syndrome, periodic Cushing's syndrome, exogenous cortisol excess, cortisol excess, hyperglycemia, multiple endocrine neoplasia type 1, McKoon-Albright syndrome, Carney complex, congenital adrenal hyperplasia, precocious puberty, and hormone-sensitive cancer in a subject requiring treatment, wherein the subject is also administered metformin, and the method is: This includes administering a therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, to a subject in need. The therapeutically effective dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, is determined via a dose-setting scheme. A method comprising administering levocetoconazole or a pharmaceutically acceptable salt thereof, thereby increasing systemic exposure to metformin by approximately twofold.

10. The method according to any one of claims 1 to 9, wherein the disease is selected from Cushing's syndrome and periodic Cushing's syndrome.

11. The method according to claim 10, wherein the disease is persistent or relapsing Cushing's syndrome.

12. The method according to claim 10 or 11, wherein the subject has had prior surgery or radiation to treat Cushing's syndrome in the subject.

13. The method according to claim 10 or 11, wherein the subject has not had any prior surgery or radiation to treat Cushing's syndrome in the subject.

14. The method according to any one of claims 3, 4, 7, 8, or 9, wherein the dose of metformin or a pharmaceutically acceptable salt thereof is reduced.

15. The method according to claim 14, wherein the dose of metformin or a pharmaceutically acceptable salt thereof is reduced by at least 25%.

16. The method according to claim 14, wherein the dose of metformin or a pharmaceutically acceptable salt thereof is reduced by at least 50%.

17. The method according to any one of claims 3, 4, 7, 8, or 9, wherein the frequency of administration of metformin or a pharmaceutically acceptable salt thereof is reduced.

18. The method according to any one of claims 1 to 17, wherein the dose setting scheme includes increasing the dose of levocetoconazole or a pharmaceutically acceptable salt thereof until one or more of the following conditions are met: (1) the subject has a sufficient response; (2) the maximum designated dose is reached; or (3) a dose limiting event occurs.

19. The aforementioned dose setting scheme is Administering a first dose of levocetoconazole, or a pharmaceutically acceptable salt thereof, for a first period of time; To increase the aforementioned dose by an amount equal to the increment value; This includes determining whether the subject is tolerable to the increased dose; The cycle is repeated as long as the subject tolerates the increased dose, and the increment value in each cycle iteration is the same or different; The method according to any one of claims 1 to 18, wherein if the subject does not tolerate the increased dose, the patient's dose is equal to the difference between a further increased dose and the increment value for the final cycle iteration.

20. The method according to claim 19, wherein the first dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg administered twice daily.

21. The method according to claim 19 or 20, wherein the increment value is 150 mg / day.

22. The method according to any one of claims 1 to 18, wherein the therapeutically effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 150 mg to 1200 mg / day.

23. The method according to any one of claims 1 to 18, wherein the therapeutically effective dose of levocetoconazole or a pharmaceutically acceptable salt thereof is 600 mg twice daily.

24. The method according to any one of claims 1 to 23, further comprising informing the subject or healthcare worker that co-administration of levocetoconazole or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof may result in increased exposure to metformin.

25. The method according to any one of claims 1 to 24, further comprising notifying the subject or healthcare worker that co-administration of levocetoconazole 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 the administration of metformin or a pharmaceutically acceptable salt thereof.

26. The method according to any one of claims 1 to 25, further comprising monitoring the serum concentration of metformin or a pharmaceutically acceptable salt thereof.

27. The method according to any one of claims 1 to 26, further comprising monitoring the subject for one or more exposure-related adverse reactions associated with the administration of metformin or a pharmaceutically acceptable salt thereof.

28. The method according to claim 27, wherein one or more of the exposure-related adverse reactions are selected from diarrhea, nausea / vomiting, flatulence, asthenia, indigestion, abdominal discomfort, lactic acidosis, and headache.

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