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WO2022101303A1 - Méthodes d'administration du rélugolix - Google Patents

Méthodes d'administration du rélugolix Download PDF

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Publication number
WO2022101303A1
WO2022101303A1 PCT/EP2021/081304 EP2021081304W WO2022101303A1 WO 2022101303 A1 WO2022101303 A1 WO 2022101303A1 EP 2021081304 W EP2021081304 W EP 2021081304W WO 2022101303 A1 WO2022101303 A1 WO 2022101303A1
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Prior art keywords
inhibitor
pharmaceutically acceptable
acceptable salt
methoxyurea
tetrahydrothieno
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2021/081304
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English (en)
Inventor
Elizabeth M. MIGOYA
David B. BUCKLEY
Juan Camilo ARJONA FERREIRA
Tien-Yi Lee
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Sumitomo Pharma Switzerland GmbH
Original Assignee
Myovant Sciences GmbH
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Priority to JP2023528189A priority Critical patent/JP2023549196A/ja
Priority to EP21810968.4A priority patent/EP4243829A1/fr
Publication of WO2022101303A1 publication Critical patent/WO2022101303A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • Compound 1 N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea, is a gonadotropin-releasing hormone (GnRH) antagonist being developed as a new pharmaceutical agent useful for treating various conditions including heavy menstrual bleeding and other symptoms associated with uterine fibroids, pain and other symptoms associated with endometriosis, and prostate cancer. Compound 1 may also useful to treat other diseases or disorders.
  • GnRH gonadotropin-releasing hormone
  • Other methods of preparing Compound 1, and intermediates and crystalline forms thereof can be found in U.S. Patent No.9,758,528, U.S. Patent No.10,150,778, U.S. Patent No. 10,464,945, U.S. Patent No.10,544,160, and U.S. Patent No.11,053,257.
  • Solid preparations of Compound 1 can be found in U.S. Patent No.10,350,170.
  • Compound 1 is useful for treating prostate cancer.
  • Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the United States. According to the National Cancer Institute, approximately 2.9 million men are currently living with prostate cancer in the United States, and approximately 180,000 men are newly diagnosed in the United States each year.
  • Compound 1 is useful for treating hormone-sensitive diseases of the female reproductive system. These diseases have a significant effect on the quality of life for many women. In these conditions, hormones such as estrogens and progesterone can have an impact on the severity and/or frequency of symptoms.
  • hormones such as estrogens and progesterone can have an impact on the severity and/or frequency of symptoms.
  • uterine fibroids are benign, estrogen-sensitive tumors (myomas) that grow in the muscular wall of the uterus in approximately 25% of women of reproductive age. Most uterine fibroids are asymptomatic, but approximately 25% of women with uterine fibroids develop symptoms requiring treatment.
  • estrogens, progesterone and human growth hormone may all play important roles in the regulation of fibroid growth.
  • uterine fibroids are benign tumors that are often asymptomatic, they can cause debilitating symptoms such as abnormal uterine bleeding, heavy or painful periods, anemia, abdominal pain, backache, increased abdominal girth and bloating, urinary frequency or retention, constipation or painful defecation, pregnancy loss, painful intercourse and, in some cases, infertility.
  • Endometriosis is a gynecological medical condition in which cells from the lining of the uterus grow outside the uterine cavity, most commonly on the ovaries.
  • Endometriosis is a chronic and usually progressive disease that occurs almost exclusively in women of reproductive age and can cause nonmenstrual pelvic pain, dysmenorrhea, dyspareunia, and infertility. It has an estimated prevalence of 10% among fertile women and from 20% to 40% among infertile women. Endometriosis lesions outside the uterus exhibit a pattern of hormonal responsiveness similar to that of the lining of the uterus. During the menstrual cycle, the lesions grow, differentiate and shed into the abdomen, thereby inducing a cascade of inflammatory events that may lead to nonmenstrual pelvic pain, pain during menstruation, painful intercourse and, in some cases, infertility.
  • Adenomyosis is a condition distinct from endometriosis where endometrial tissue is found within the myometrium (muscular layer of the uterus). Patients with adenomyosis may experience heavy menstrual bleeding (HMB) and chronic pain, among other symptoms.
  • HMB menstrual bleeding
  • oral preparations comprising about 1 mg to about 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2, 4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of prostate cancer in a subject in need thereof.
  • a combined oral preparation for use in a method of treating prostate cancer in a subject in need thereof comprises administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about Img to about 360 mg of N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3- pyridazinyl)-2,4-dioxo- 1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering to the subject once-daily for 24 consecutive weeks or greater for a second treatment period, an oral maintenance dose combination having about 1 mg to about 120 mg of N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl
  • a combined oral preparation comprises about 1 mg to about 120 mg N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp and a CYP3A inhibitor, for use in a method of treating prostate cancer in a subject in need thereof, the method comprising: administering the combined oral preparation to the subject once daily; suspending administration of the combined oral preparation for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral preparation at the end of the suspension period
  • a method treating prostate cancer in a subject in need thereof comprises administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about 1 mg to about 360 mg of N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1 ,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering to the subject once-daily for 24 consecutive weeks or greater for a second treatment period, an oral maintenance dose combination having about 1 mg to about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6
  • a method for treating prostate cancer in a subject in need thereof comprises administering to the subject once daily a combined oral preparation comprising about 1 mg to about 120 mg of N-(4-(1-(2,6 -difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-S-pyridazinyl)-2, 4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; suspending administration of the combined oral combination for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral combination at the end of the suspension period.
  • oral preparations comprising about 1 mg to about 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3- pyridazinyl)-2, 4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of one or more of uterine fibroids, endometriosis, adenomyos
  • a method for treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman comprising administering to the pre- menopausal woman, once daily, a combination comprises about 1 mg to about 40 mg of N-(4-(1- (2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about
  • FIG. 1A and FIG. IB show the time profiles of mean plasma concentrations of unchanged Compound 1 after administration of Compound 1 (20 mg alone) and administration of Compound 1 (20 mg in a steady state of erythromycin, 1200 mg/day), from 0-120 hours and 0-24 hours, respectively.
  • FIG. 1C shows the same data presented in a log- linear scale.
  • FIG. 2 shows the transcellular transport of [3H] digoxin (3 ⁇ mol/L), [3H] estrone 3- sulfate (0.1 ⁇ mol/L), [14C]antipyrine (10 ⁇ mol/L) and [14C]mannitol (10 ⁇ mol/L) across Caco- 2 cell monolayers
  • FIG. 3 shows the transcellular transported amount of [14C]Compound 1 (3 ⁇ mol/L) across Caco-2 cell monolayers.
  • FIG. 4A shows Compound 1 flux in Caco-2 cells.
  • FIG. 4B shows digoxin flux in Caco- 2 cells.
  • FIG. 5 shows a summary of dosing schedules of the drug interaction studies described in Examples 1-4. Labels indicate on which days relugolix was co-administered.
  • FIG. 6 shows a forest plot of geometric mean ratios and 90% CI for the AUC and C max of Compound 1 upon co-administration with P-gp and/or CYP3A inhibitors and inducers.
  • GnRH receptor antagonist an orally active GnRH antagonist
  • Compound 1 or a pharmaceutically acceptable salt thereof
  • P-gp inhibitor or a combination of a P-gp inhibitor and CYP3A inhibitor once-daily for the treatment of prostate cancer.
  • a hormone replacement medicament e.g., estradiol or an estradiol equivalent, or a progestin, or a combination thereof
  • Compound 1 also known as relugolix, and pharmaceutical compositions including Compound 1 can be produced by methods described in U.S. Patent 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 9,346,822, U.S. Patent No. 9,758,528, U.S. Patent 8,735,401, and WO 2016136849, the disclosures of which are herein incorporated by reference.
  • Compound 1 is a pharmaceutically acceptable salt.
  • “Physiologically acceptable,” “pharmaceutically acceptable,” or “pharmacologically acceptable” compounds and compositions may include materials which are not biologically, or otherwise, undesirable.
  • the material may be administered to an individual without causing any substantially undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the pharmaceutically acceptable salt of Compound 1 is a pharmaceutically acceptable acid addition salt.
  • Such salts include, but are not limited to, salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like), and salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, and the like).
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like
  • organic acids e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic
  • amounts of Compound 1 disclosed refer to the amount of Compound 1 free form present in the formulation.
  • the term “corresponding amount” as used herein refers to the amount of a pharmaceutically acceptable salt of Compound 1 required to obtain the amount of Compound 1 free form recited in the formulation. It would be clear to one of skill in the art how to calculate the “corresponding amount” of the salt of a compound, such as the corresponding amount of the pharmaceutically acceptable salt of Compound 1, taking into account the difference in molecular weight between the free form of a compound and a salt form. For example, 80.0 mg of compound free base, would correspond to 84.7 mg of the HQ salt.
  • Compound 1 has been characterized as an orally active, nonpeptide, GnRH antagonist.
  • Compound 1 has been shown to antagonize GnRH through the GnRH receptors, which are present in the pituitary anterior lobe basophiles (secretory cells), and inhibits the GnRH- stimulated secretion of LH and FSH from these cells.
  • the drug decreases blood concentrations of hormones, including testosterone, estradiol and progesterone.
  • the present disclosure provides methods and uses of treating a disorder comprising administering a therapeutically effective amount of Compound 1 and a P-glycoprotein (P-gp) inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; or combined oral preparations comprising Compound 1 and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor, described herein to thereby treat the disorder in a subject in need thereof.
  • Administering Compound 1 with a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor could significantly lower the dose of Compound 1 and therefore lower the total exposure of the patient to the drug while maintaining efficacy.
  • Compound 1 is a substrate.
  • P-gp is a transmembrane transporter that contributes to the active apical efflux of substrates from within enterocytes into the intestinal lumen, thereby limiting the oral bioavailability of substrate drugs.
  • Compound 1 is also a substrate for the drug metabolizing enzymes CYP3A and CYP2C8 in NADPH-fortified human liver microsomes (HLM), with each contributing to the hepatic metabolism of Compound 1 in vitro by 45% and 37%, respectively.
  • HLM human liver microsomes
  • Reducing or minimizing the intestinal efflux (i.e., via P-gp) and/or first pass metabolism of Compound 1 may enable administration of lower oral doses of Compound 1 to achieve systemic (i.e., plasma) exposures considered sufficient to achieve desired pharmacodynamic effects.
  • the methods of this disclosure may accomplish the above. Co-administration of Compound 1 with a P-gp or combined P-gp/CYP3A inhibitor can result in inhibition of the primary pathways limiting the oral absorption/ first pass metabolism of Compound 1, and may enable administration of lower oral doses of Compound 1 to achieve desired systemic exposures compared with oral administration of Compound 1 in the absence of an inhibitor.
  • Lower overall exposure of Compound 1, while maintaining the required efficacy, may be beneficial to the patient for a number of reasons. For instance, being able to avoid the effects of P-gp export on bioavailability may allow the use of Compound 1 with other drugs that induce the activity of P-gp. Further, minimizing the absolute dose of drug administered may mitigate side effects that might otherwise be present with long-term, high-dose exposure. Lowering the absolute dose of Compound 1 administered over a course of treatment also has commercial and economic benefits. Specifically, it may reduce the overall cost of manufacturing the drug product itself, and relatedly reduces waste in the manufacturing process (e.g., less reagents, less solvent).
  • co-administration of Compound 1 with drugs that inhibit P-gp, or CYP3A, or both may cause increases in Compound 1 exposure as described above (e.g., erythromycin).
  • drugs that are inhibitors of P-gp, or CYP3A a dose-staggering strategy could be employed.
  • the timing of administration of Compound 1 and the co-administered drug would be separated by a sufficient amount of time (e.g., 4 or 8 hours) to minimize or reduce the pharmacokinetic interactions responsible for the increases in Compound 1 exposure and, as such, enabling co-administration of Compound 1 with inhibitor drugs whereby maintaining Compound 1 exposures in a range for desired efficacy and safety.
  • the disorder is a hormone-dependent condition.
  • Hormone-dependent conditions may include sex hormone- dependent cancer (e.g., prostate cancer, uterine cancer, breast cancer, and ovarian cancer), bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, hysteromyoma (uterine fibroids), adenomyoma, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flash, endometriosis, adenomyosis, heavy menstrual bleeding, and symptoms associated with these conditions.
  • sex hormone- dependent cancer e.g., prostate cancer, uterine cancer, breast cancer, and ovarian cancer
  • prostatic hypertrophy e.g., hysteromyoma (uterine fibroids), adenomyoma, metrofibro
  • Such symptoms may include anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, constipation, anxiety, sleep disturbance, decrease in quality of life, difficulty with activities of daily living, female sexual dysfunction, and depression.
  • the hormone-dependent condition is prostate cancer, uterine cancer, breast cancer, or ovarian cancer. Additional disorders that Compound 1 is useful for treating are described in U.S. Patent 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, U.S. Patent No. 10,449,191, U.S. Appl. No. 16/563,161, U.S. Pub. No.
  • the hormone- dependent condition is prostate cancer. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is uterine cancer. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is breast cancer. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is ovarian cancer. In some embodiments of the methods and uses of the disclosure, the hormone- dependent condition is uterine fibroids. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is heavy menstrual bleeding associated with uterine fibroids. In some embodiments of the methods and uses of the disclosure, the hormone- dependent condition is pain or other symptoms associated with uterine fibroids.
  • the hormone-dependent condition is endometriosis. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is adenomyosis. In some embodiments of the methods and uses of the disclosure, the hormone-dependent condition is heavy menstrual bleeding.
  • a “patient” or “subject” is a mammal.
  • mammals may include, but are not limited to, any member of the class Mammalia including humans; non-human primates such as chimpanzees, monkeys, baboons, and rhesus monkeys; cattle, horses, sheep, goats, and swine; rabbits, dogs, and cats; and rodents such as rats, mice and guinea pigs.
  • the patient or subject is a human.
  • the patient is a man with a hormone-dependent conditions.
  • the patient is a man with prostate cancer.
  • a patient is a woman with a hormone- dependent condition.
  • the patient is a pre-menopausal woman with uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, pain associated with endometriosis, or adenomyosis.
  • kits for treating prostate cancer comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the prostate cancer is hormone dependent prostate cancer.
  • “Hormone dependent prostate cancer,” “hormone sensitive prostate cancer,” “androgen dependent prostate cancer,” or “androgen sensitive prostate cancer” may refer to prostate cancer needing relatively high levels of androgens to grow early in its development. Such prostate cancer may be referred to as androgen/hormone dependent or androgen/hormone sensitive because treatments that decrease androgen levels or block androgen activity can effectively inhibit its growth.
  • the prostate cancer is advanced prostate cancer.
  • Prostate cancer is typically considered “advanced” if it has spread beyond the prostate gland and the area around the prostate. It may spread to nearby tissues, lymph nodes, bones, or other parts of the body. When it spreads to tissues directly adjacent to the prostate gland, it is often referred to as “locally advanced prostate cancer.” When it spreads beyond the tissues directly adjacent to the prostate gland, it is typically referred to as “metastatic prostate cancer.” Metastatic prostate cancer typically may have spread to the bone, lung, liver, brain, lymph nodes outside the pelvis, or other organs, and may be hormone-sensitive.
  • prostate cancer PSA biochemical relapse following primary surgical or radiation therapy of curative intent; newly diagnosed metastatic prostate cancer; advanced localized disease for which immediate radiation or surgical therapy is not indicated, or men whose disease progresses after prostatectomy or radiation.
  • the clinical recurrence of advanced prostate cancer occurs when it is associated with symptoms. Therefore, “advanced” prostate cancer may be present with or without evidence on diagnostic imaging tests and with or without clinical symptoms.
  • the treatment methods and uses of this disclosure include palliative treatment of advanced prostate cancer.
  • the prostate cancer is advanced hormone sensitive prostate cancer.
  • “Advanced hormone dependent prostate cancer,” “advanced hormone sensitive prostate cancer,” “advanced androgen dependent prostate cancer,” or “advanced androgen sensitive prostate cancer” as used herein may refer to prostate cancer that has spread beyond the prostate gland and the area around the prostate. The growth of prostate cancer is suppressed or the cancer may even shrink when androgen levels are suppressed (e.g., hormonal therapy that lowers serum testosterone below castration levels ⁇ 50 ng/dL).
  • the prostate cancer is locally advanced, advanced castration resistant, or recurrent.
  • “Locally advanced prostate cancer” may refer to cancer that has started to break out of the prostate, or has spread to the area just outside, or nearby, the prostate. It may also be characterized as stage T3 or T4 prostate cancer. It may have spread to one or more of e.g., the prostate capsule, the seminal vesicles, the pelvic lymph nodes, the bladder, and the back passage (rectum).
  • Advanced castration-resistant prostate cancer or “advanced hormone -resistant prostate cancer” may refer to castration- resistant prostate cancer that has spread beyond the prostate gland and the area around the prostate.
  • Recurrent prostate cancer may refer to prostate cancer that has been detected or has returned following initial treatment, such as after surgery, radiation therapy, and/or hormone therapy. Recurrent prostate cancer may have a biochemical and/or clinical recurrence. Some patients may only have a rise in PSA level as evidence of the recurrent prostate cancer (biochemical recurrence) and others will have evidence of recurrent prostate cancer on x-rays and scans (clinical recurrence). “Biochemical recurrence” may refer to the return of the prostate cancer after initial treatment, but the return cannot be measured by standard imaging methods.
  • prostate cancer may be present with or without evidence on diagnostic imaging tests and with or without clinical symptoms.
  • the return of the prostate cancer is identified by a rise in PSA as determined by a blood test.
  • the criteria for is biochemical recurrence may include a rise in PSA of “nadir + 2 ng/mL” for relapse after radiation therapy, > 0.2 ng/mL if recurrent after prostatectomy, and > 2 ng/mL if recurrent after all other treatments.
  • “Clinical recurrence” may refer to the return of clinical symptoms associated with growth or spread of prostate cancer after initial treatment of prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer.
  • the prostate cancer is castration-resistant metastatic prostate cancer.
  • the prostate cancer is castration-resistant non-metastatic prostate cancer.
  • “Castration-resistant prostate cancer” or “hormone-resistant prostate cancer” may refer to prostate cancer that continues to grow even when androgen levels in the body are extremely low or undetectable. For example, with castration-resistant prostate cancer, PSA may increase or the cancer may show other signs of growing even after using hormone therapy to bring serum testosterone to castration levels ( ⁇ 50 ng/dL).
  • Castration-resistant prostate cancer For castration- resistant prostate cancer, hormonal therapy (e.g., suppression of serum testosterone levels) is continued, and additional therapies are added to the treatment protocol in addition to the continued administration of drugs used to lower serum testosterone.
  • Castration-resistant prostate cancer may be either metastatic (castration-resistant metastatic prostate cancer) or non- metastatic (castration-resistant non-metastatic prostate cancer) prostate cancer.
  • “Metastatic castration resistant prostate cancer” or “castration-resistant metastatic prostate cancer” may refer to prostate cancer that has spread beyond the prostate and continues to grow and progress (including but not limited to a rise in PSA) in the setting of suppressed androgen levels (i.e., hormonal therapy that lowers serum testosterone below castration levels ⁇ 50 ng/dL).
  • once-daily administration of an oral formulation comprising Compound 1, or a pharmaceutically acceptable salt thereof reduces serum FSH levels and, therefore, may reduce the rate of subjects who develop castration-resistant prostate cancer. In some embodiments, once-daily administration of an oral formulation comprising Compound 1, or a pharmaceutically acceptable salt thereof, reduces serum FSH levels and, therefore, may slow the development of castration-resistant prostate cancer.
  • the prostate cancer is hormone-sensitive metastatic prostate cancer. In some embodiments of the methods and uses described herein, the prostate cancer is hormone-sensitive non-metastatic prostate cancer.
  • the prostate cancer is hormone naive advanced prostate cancer.
  • “Hormone naive advanced prostate cancer” may be subdivided into two disease states: biochemical recurrence or traditional metastatic prostate cancer and may be characterized by no prior hormonal therapy or androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the combined oral preparations of the methods and uses described herein comprise about 1 mg to less than about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • “combined oral preparation” can encompasses the terms “oral load dose combination,” “oral load dose formulation,” “oral load dosage,” “oral load dose,” “oral maintenance dose combination,” “oral maintenance dose formulation,” “oral maintenance dosage,” and the like, unless clearly dictated otherwise by context.
  • oral load dose combination is an initial dose of a Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor, that may be given at the beginning of a course of treatment before changing to a different maintenance dose. As described herein, it is typically a larger initial dose of Compound 1, or a pharmaceutically acceptable salt thereof, and, optionally, a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor, or series of such doses given to rapidly achieve a therapeutically effective amount of drug in the body.
  • a “therapeutically effective amount” may refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder.
  • a therapeutically effective dose for prostate cancer treatment includes where the treatment brings about an amelioration of one or more symptoms of the prostate cancer, slows the progression of the prostate cancer, results in remission, etc.
  • oral maintenance dose combination is the dose of Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor, given after a certain period of taking the load dosage and is typically a lower amount of Compound 1, or a pharmaceutically acceptable salt thereof, than the load dosage yet maintains the desired therapeutic effect.
  • the combined oral preparations of the methods and uses described herein comprise less than about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and from about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor. In some embodiments, the combined oral preparations of the methods and uses described herein comprise from about 1 mg to about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and from about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the combined oral preparations of the methods and uses described herein comprise from about 1 mg to about 120 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a C YP3 A inhibitor.
  • the combined oral preparations of the methods and uses described herein comprise from about 1 mg to about 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor In some embodiments, the combined oral preparations of the methods and uses described herein comprise less than about 120 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a C YP3A inhibitor.
  • the combined oral preparations of the methods and uses described herein comprise less than about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor. In some embodiments, the combined oral preparations of the methods and uses described herein comprise about 60 mg to about 340 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the combined oral preparations of the methods and uses described herein comprise about 20 mg to about 100 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor. In some embodiments, the combined oral preparations of the methods and uses described herein comprise about 4 mg to about 20 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor.
  • the combined oral preparations of the methods and uses described herein comprise about 20 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the disclosure also provides methods and uses for treating prostate cancer in a subject in need thereof comprising administering once-daily combined oral preparations comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • Once-daily administration of combined oral preparations comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor can be suspended for a suspension period, leading to an increase in the subject’s serum testosterone levels.
  • once-daily administration of combined oral preparations comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor resumes at the end of the suspension period.
  • once-daily administration of combined oral combinations comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor does not resume after it is suspended.
  • the suspension period is discontinued when the subject experiences return of symptoms of prostate cancer.
  • a combined oral preparation of the methods or uses described herein is administered for 12 consecutive weeks or greater, 24 consecutive weeks or greater, 48 consecutive weeks or greater, 52 consecutive weeks or greater, 72 consecutive weeks or greater, or 96 consecutive weeks or greater.
  • This disclosure provides a method for treating prostate cancer in a subject in need thereof, the method comprising administering to the subject once daily a combined oral preparation comprising less than 360 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; suspending administration of the combined oral combination for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral combination at the end of the suspension period.
  • a method for treating prostate cancer in a subject in need thereof comprising administering to the subject once daily a combined oral preparation comprising from about 1 mg to about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; suspending administration of the combined oral combination for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral combination at the end of the suspension period.
  • the suspension period is up to 52 weeks, up to 36 weeks, up to 24 weeks, up to 12 weeks, up to 8 weeks, or up to 4 weeks. In some embodiments, the suspension period is discontinued when the subject experiences return of symptoms of prostate cancer. In some embodiments, administration is suspended after at least 24 consecutive weeks of treatment, after at least 36 consecutive weeks of treatment, or after at least 52 consecutive weeks of treatment.
  • the methods and uses include administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about 1 mg to about 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering once-daily to the subject for 4 consecutive weeks or greater, 8 consecutive weeks or greater, 12 consecutive weeks or greater, 16 consecutive weeks or greater, 20 consecutive weeks or greater, or 24 consecutive weeks or greater, an oral maintenance dose combination having from about 1 mg to about 120 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor.
  • the methods and uses include administering to the subject once-daily for at least 24 consecutive weeks, an oral maintenance dose combination having about 20 mg of Compound 1 and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the oral load dose combination further comprises about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • the oral load dose combination comprises about 10 mg to about 350 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 350 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 300 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 250 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 200 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination comprises about 20 mg to about 150 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 50 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 30 mg to about 350 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 30 mg to about 300 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination comprises about 30 mg to about 250 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 30 mg to about 200 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 30 mg to about 150 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 30 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 20 mg to about 50 mg.
  • the oral load dose combination comprises about 40 mg to about 350 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 40 mg to about 300 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 40 mg to about 250 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 40 mg to about 200 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 40 mg to about 150 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination comprises about 40 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 40 mg to about 50 mg. In some embodiments, the oral load dose combination comprises about 50 mg to about 350 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 300 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 250 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination comprises about 50 mg to about 200 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 150 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 180 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 240 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination comprises about 50 mg to about 70 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 60 mg to about 70 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 50 mg to about 80 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral load dose combination comprises about 60 mg to about 80 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral maintenance dose combination comprises about 10 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 90 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 80 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 70 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 60 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral maintenance dose combination comprises about 10 mg to about 50 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 30 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 10 mg to about 20 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 100 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral maintenance dose combination comprises about 20 mg to about 90 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 80 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 70 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 60 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 50 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral maintenance dose combination comprises about 20 mg to about 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 20 mg to about 30 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 15 mg to about 30 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 15 mg to about 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the oral maintenance dose combination comprises about 15 mg to about 80 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • the oral load dose combination and oral maintenance dose combination may vary, the oral load dose combination would be greater than the oral maintenance dose combination.
  • the disclosure also provides methods and uses for treating prostate cancer in a subject in need thereof in which castration is achieved.
  • castration generally refers to serum testosterone levels of about ⁇ 50 ng/dL and “profound castration” generally refers to serum testosterone levels of about ⁇ 20 ng/dL.
  • profound castration is achieved within 24 to 48 hours after commencing administration and is maintained until the end of administration.
  • a combined oral preparation for use in a method of treating prostate cancer in a subject in need thereof comprises administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination, and administering to the subject once-daily for 24 consecutive weeks or greater for a second treatment period, an oral maintenance dose combination.
  • an oral load dose combination of the disclosure comprising less than 360 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; once- daily for 1-3 days at the beginning of treatment, and once-daily administration of an oral maintenance dose combination of the disclosure comprising less than 120 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; starting on the day after administering the last dose of the oral load dose combination, and continuing for a set treatment period (e.g., at least 4 consecutive weeks or greater, at least 8 consecutive weeks or greater, at least 12 consecutive weeks or greater, at least 16 consecutive weeks or greater, at least 20 consecutive weeks or greater,
  • a set treatment period e.g., at least 4 consecutive weeks
  • administering a preparatory dose of a P- gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor alone prior to commencing treatment with the combined oral preparations for any of the methods or uses herein.
  • administration of the combined oral preparation is preceded by administration of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor alone.
  • administration of the combined oral preparation is preceded by at least 5 days of daily administration of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor alone.
  • the preparatory dose of the P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor is about 0.01 mg to about 1000 mg.
  • Compound 1 or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor, for the manufacture of a medicament for the treatment of prostate cancer.
  • kits for treating one or more of uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a P-gp inhibitor.
  • a pre-menopausal woman may, for example, include a woman who has started having menstrual periods but who has not yet reached menopause.
  • a pre-menopausal woman may include a woman who is experiencing peri-menopause. Whether a woman is pre-menopausal may be determined by evaluating a woman’s medical history, for example by asking questions to the woman. In a woman who has not had a period for a year or longer, FSH levels in serum greater than or equal to 30 mIU/mL may also indicate the woman has reached menopause
  • the methods provided herein also include co-administration of a hormone replacement medicament (e.g., a combination of an estradiol or estradiol equivalent and a progestin), also referred to herein as add-back.
  • a hormone replacement medicament e.g., a combination of an estradiol or estradiol equivalent and a progestin
  • uterine fibroids adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman
  • administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with estradiol or a corresponding amount of estradiol equivalent; a progestin; and a P-gp inhibitor and a CYP3 A inhibitor.
  • the combination may be administered, for example, as either a fixed dose or in two or more separate dosage forms that are co- administered. This may be desirable, for example, in a woman with severe symptoms, or a plurality of symptoms, or with a desire to more quickly alleviate one or more symptoms.
  • Administration of Compound 1, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor , without a hormone replacement medicament may result in lower serum estradiol and/or serum progesterone levels more rapidly than administration of the combination, and therefore may more quickly alleviate one or more symptoms of an estrogen- or progesterone-sensitive condition.
  • Administration of the combined oral preparation as in the method of treating uterine fibroids, heavy menstrual bleeding associated with uterine fibroids, pain associated with uterine fibroids, or a woman with symptomatic uterine fibroids may result in suppression of the pre- menopausal woman’s ovarian estrogen production.
  • the pre-menopausal woman’s ovarian estrogen production is suppressed.
  • uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman comprising administering to the pre-menopausal woman, once daily, a combination comprising: less than 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman comprising administering to the pre-menopausal woman, once daily, a combination comprising: about 1 mg to about 40 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • oral preparations comprising less than 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of one or more of uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre- menopausal woman.
  • oral preparations comprising from about 1 mg to about 40 mg of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of one or more of uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman.
  • the combined oral preparation comprises from about 1 mg to about 40 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 1 mg to about 30 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 1 mg to about 20 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 1 mg to about 10 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 2 mg to about 40 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 2 mg to about 30 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 2 mg to about 20 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 2 mg to about 10 mg of Compound 1.
  • the combined oral preparation comprises from about 5 mg to about 40 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 5 mg to about 30 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 5 mg to about 20 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 5 mg to about 10 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 10 mg to about 40 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 10 mg to about 30 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 10 mg to about 20 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 10 mg to about 15 mg of Compound 1.
  • the combined oral preparation comprises from about 20 mg to about 40 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 20 mg to about 30 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 15 mg to about 25 mg of Compound 1. In some embodiments, the combined oral preparation comprises from about 20 mg to about 25 mg of Compound 1.
  • the hormone replacement medicament comprises about 0.01 mg to about 5 mg of a progestin.
  • the hormone replacement medicament comprises about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg progestin.
  • the hormone replacement medicament comprises about 0.1 mg to about 0.5 mg of a progestin, for example about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0.5 mg of progestin.
  • the progestin is a norethindrone salt, for example norethindrone acetate.
  • the hormone replacement medicament comprises about 0.5 mg of norethindrone acetate.
  • the combination comprises between about 0.625 mg to about 5 mg nomegestrol acetate, or about 0.05 mg to about 0.5 mg levonorgestrel, or about 0.5 to about 5 mg dienogest.
  • the hormone replacement medicament comprises from about 0.5 to about 2 mg of estradiol, or a corresponding amount of estradiol equivalent.
  • the hormone replacement medicament comprises from about 0.5 mg to about 1 mg, from about 0.5 mg to about 1.5 mg, from about 1 mg to about 1.5 mg, from about 1 mg to about 2 mg, from about 1.5 mg to about 2 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg estradiol, or a corresponding amount of an estradiol equivalent.
  • the hormone replacement medicament comprises about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent, and about 0.01 mg to about 5 mg of a progestin.
  • the progestin is norethindrone or a salt thereof in an amount of about 0.1 mg to about 0.5 mg.
  • the progestin is norethindrone acetate (NETA).
  • the combination comprises about 0.5 mg of NETA.
  • the pre-menstrual woman has a maximum NRS score of 1 or less for uterine fibroid pain 6 weeks, 8 weeks, or 10 weeks, after beginning treatment; or has an increase in the number of days with an NRS score of 0 within 6 weeks, 8 weeks, or 10 weeks, after beginning treatment, compared to the 6 weeks, 8 weeks, or 10 weeks immediately before beginning treatment.
  • the mean NRS score over 35 days during treatment is reduced by at least 30% within 6 weeks, 8 weeks, or 10 weeks after beginning treatment.
  • the pre-menopausal woman has a maximum NRS score for uterine fibroid associated pain of 4 weeks or greater, 6 weeks or greater, 8 weeks or greater, or 10 weeks or greater immediately before beginning treatment.
  • Ameliorating pain may include, for example, reducing pelvic pain (including dysmenorrhea), non-menstrual pelvic pain, or dyspareunia
  • the pre-menopausal woman experiences an improvement of one or more symptoms during the treatment, or after the treatment.
  • the one or more symptoms may be selected from the group consisting of anemia, heavy menstrual bleeding, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, constipation, anxiety, sleep disturbance, quality of life, activities of daily living, female sexual dysfunction and depression.
  • Pain may be, for example, back pain, pelvic pain, uterine pain, chronic pain, pain with defecation, pain with urination, or dyspareunia, or any combinations thereof.
  • methods of treating one or more symptoms associated with uterine fibroids in a pre-menopausal woman in need thereof comprising administering to the pre-menopausal woman once-daily a combination of Compound 1, or a pharmaceutically acceptable salt thereof, a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor, and a hormone replacement medicament.
  • P-gp is a transmembrane transporter that contributes to efflux of substrates, including drugs like Compound 1, from within enterocytes into the intestinal lumen, thereby limiting the oral bioavailability.
  • CYP3A is a member of the cytochrome P450 family of metabolic enzymes that likewise limits oral bioavailability of certain drug substrates.
  • a P-gp inhibitor of Table 1 is also a CYP3A inhibitor.
  • a CYP3A inhibitor from Table 2 is also a P-gp inhibitor.
  • the combined oral preparations of the disclosure comprise a P- gp inhibitor from Table 1.
  • the combined oral preparations of the disclosure comprise a combination of a P-gp inhibitors from Table 1 and a CYP3A inhibitor from Table 2.
  • the P-gp inhibitor is from Table 1.
  • the P-gp inhibitor is from Table 1 and the CYP3A inhibitor from Table 2.
  • the combined oral preparations of the disclosure comprise about 0.01 mg to about 1000 mg; about 0.01 mg to about 0.1 mg ; 0.01 mg to about 1 mg; about 0.01 mg to about 5 mg; about 1 mg to about 5 mg; about 1 mg to about 10 mg; 10 mg to about 20 mg; about 20 mg to about 30 mg; about 30 mg to about 40 mg; about 40 mg to about 50 mg of a P-gp inhibitor; about 50 mg to about 60 mg; about 60 mg to about 70 mg; about 70 mg to about 80 mg; about 80 mg to about 90 mg; about 90 mg to about 100 mg; about 1 mg to about 100 mg; about 100 mg to about 1000 mg; about 200 mg to about 1000 mg; about 300 mg to about 1000 mg; about 300 mg to about 1000 mg; about 400 mg to about 1000 mg; about 500 mg to about 1000 mg; about 600 mg to about 1000 mg; about 700 mg to about 1000 mg; about 800 mg to about 1000 mg; about 900 mg to about 1000 mg; about 1 mg to about 200 mg; about 200 mg to about 400 mg;
  • the methods and uses described herein for treating prostate cancer in a subject in need thereof comprise administering about 0.01 mg to about 100 mg; about 0.01 mg to about 0.1 mg ; 0.01 mg to about 1 mg; about 0.01 mg to about 5 mg; about 1 mg to about 5 mg; about 1 mg to about 10 mg; 10 mg to about 20 mg; about 20 mg to about 30 mg; about 30 mg to about 40 mg; about 40 mg to about 50 mg of a P-gp inhibitor; about 50 mg to about 60 mg; about 60 mg to about 70 mg; about 70 mg to about 80 mg; about 80 mg to about 90 mg; about 90 mg to about 100 mg; about 1 mg to about 100 mg; about 100 mg to about 1000 mg; about 200 mg to about 1000 mg; about 300 mg to about 1000 mg; about 300 mg to about 1000 mg; about 400 mg to about 1000 mg; about 500 mg to about 1000 mg; about 600 mg to about 1000 mg; about 700 mg to about 1000 mg; about 800 mg to about 1000 mg; about 900 mg to about 1000 mg; about 1 mg
  • an oral load dose combination or an oral maintenance dose combination comprises about 0.01 mg to about 100 mg; about 0.01 mg to about 0.1 mg ; 0.01 mg to about 1 mg; about 0.01 mg to about 5 mg; about 1 mg to about 5 mg; about 1 mg to about 10 mg; 10 mg to about 20 mg; about 20 mg to about 30 mg; about 30 mg to about 40 mg; about 40 mg to about 50 mg of a P-gp inhibitor; about 50 mg to about 60 mg; about 60 mg to about 70 mg; about 70 mg to about 80 mg; about 80 mg to about 90 mg; about 90 mg to about 100; about 1 mg to about 100 mg; about 100 mg to about 1000 mg; about 200 mg to about 1000 mg; about 300 mg to about 1000 mg; about 300 mg to about 1000 mg; about 400 mg to about 1000 mg; about 500 mg to about 1000 mg; about 600 mg to about 1000 mg; about 700 mg to about 1000 mg; about 800 mg to about 1000 mg; about 900 mg to about 1000 mg; about 1 mg to about 200 mg; about 200
  • the methods and uses described herein for the treatment of women’s health indications comprise administering about 0.01 mg to about 100 mg; about 0.01 mg to about 0.1 mg ; 0.01 mg to about 1 mg; about 0.01 mg to about 5 mg; about 1 mg to about 5 mg; about 1 mg to about 10 mg; 10 mg to about 20 mg; about 20 mg to about 30 mg; about 30 mg to about 40 mg; about 40 mg to about 50 mg of a P-gp inhibitor; about 50 mg to about 60 mg; about 60 mg to about 70 mg; about 70 mg to about 80 mg; about 80 mg to about 90 mg; about 90 mg to about 100 mg; about 1 mg to about 100 mg; about 100
  • Embodiment I-1 A combined oral preparation comprising about 1 mg to about 360 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo- 1 ,2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of prostate cancer in a subject in need thereof.
  • Embodiment I-2 A combined oral preparation for use in a method of treating prostate cancer in a subject in need thereof, comprising: administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about Img to about 360 mg of N-(4-(1-(2,6- difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1, 2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof;; and administering to the subject once-daily for 24 consecutive weeks or greater for a second treatment period, an oral maintenance dose combination having about 1 mg to about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-(((1-(
  • Embodiment I-3 A combined oral preparation comprising about 1 mg to about 120 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4- dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp and a CYP3A inhibitor, for use in a method of treating prostate cancer in a subject in need thereof, the method comprising: administering the combined oral preparation to the subject once daily; suspending administration of the combined oral preparation for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral preparation at the end
  • Embodiment I-4 A method of treating prostate cancer in a subject in need thereof, the method comprising administering about 1 mg to about 120 mg of N-(4-(1-(2,6-difluorobenzyl)- 5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2, 4-dioxo-1, 2, 3, 4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • Embodiment I-5 A method for treating prostate cancer in a subject in need thereof, the method comprising: administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about 1 mg to about 360 mg of N-(4-(1-(2,6- difluorobenzyl)- 5-((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2 ,4-dioxo- 1 ,2,3 ,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and administering to the subject once-daily for 24 consecutive weeks or greater for a second treatment period, an oral maintenance dose combination having about 1 mg to about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((d
  • Embodiment I-6 The combined oral preparation of embodiment I-2 or the method of embodiment I-5, wherein the oral load dose combination further comprises about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • Embodiment I-7 A method for treating prostate cancer in a subject in need thereof, the method comprising: administering to the subject once daily a combined oral preparation comprising about 1 mg to about 120 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy- 3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; suspending administration of the combined oral combination for a suspension period to allow for an increase of serum testosterone levels; and resuming administering to the subject once daily the combined oral combination at the end of the suspension period.
  • Embodiment I-8 The combined oral preparation of any one of embodiments I-1 to I-3 or the method of any one of embodiments I-4 to I-7, comprising about 20 mg of N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof.
  • Embodiment I-9 The combined oral preparation for use according to of any one of embodiments I-1 to I-3 or the method of any one of embodiments I-4 to I-7, wherein said administering comprises administration once daily of an oral load dose combination of from about 50 mg to about 100, about 50 to about 180, or from about 50 mg to about 240 mg of N-(4- (1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and 0.1 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor, for 1-3 days at the beginning of treatment.
  • Embodiment I- 10 The combined oral preparation of any one of embodiments I-1 to I- 3 or the method of any one of embodiments I-4 to I-7, wherein said administering comprises administration once daily of an oral maintenance dose combination of from about 15 mg to about 30 mg, from about 15 mg to about 40 mg, or from about 15 mg to about 80 mg of N-(4-(1- (2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a C YP3A inhibitor.
  • Embodiment I-11 The combined oral preparation of any one
  • Embodiment I-12 The combined oral preparation or the method of any of the preceding embodiments, wherein the prostate cancer is hormone dependent prostate cancer.
  • Embodiment I-13 The combined oral preparation or the method of any of the preceding embodiments, wherein the prostate cancer is advanced prostate cancer.
  • Embodiment I-14 The combined oral preparation or the method of any of the preceding embodiments, wherein the prostate cancer is metastatic, non-metastatic, locally advanced, advanced hormone sensitive, advanced castration resistant, or recurrent.
  • Embodiment I-15 The combined oral preparation or the method of any of the preceding embodiments, wherein profound castration is achieved.
  • Embodiment I-16 The combined oral preparation or the method of embodiment I-15, wherein the profound castration is achieved within 24 to 48 hours after commencing administration and is maintained until the end of administration.
  • Embodiment I-17 The combined oral preparation or the method of embodiment I-16, wherein time to castration resistance is longer than in a subject receiving GnRH agonist therapy.
  • Embodiment I-18 The combined oral preparation or the method of any of embodiments I-3, or I-7 to I-17, wherein said suspension period is up to 4 weeks, up to 12 weeks, up to 24 weeks, up to 36 weeks, or up to 52 weeks.
  • Embodiment I-19 The combined oral preparation or the method of any of embodiments I-3, or I-7 to I-17, wherein the suspension period is discontinued when the subject experiences return of symptoms of prostate cancer.
  • Embodiment I-20 The combined oral preparation or the method of any of the preceding embodiments, wherein the combined oral preparation is administered for 12 consecutive weeks or greater, 24 consecutive weeks or greater, 48 consecutive weeks or greater, 52 consecutive weeks or greater, 72 consecutive weeks or greater, or 96 consecutive weeks or greater.
  • Embodiment I-21 The combined oral preparation for use according to any one of the preceding embodiments, wherein administration is suspended after at least 24 consecutive weeks of treatment, after at least 36 consecutive weeks of treatment, or after at least 52 consecutive weeks of treatment.
  • Embodiment I-22 The combined oral preparation or the method of any of the preceding embodiments, wherein said administering is preceded by at least 5 days of daily administration of a preparatory dose of the P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor alone.
  • Embodiment I-23 The combined oral preparation of embodiment I-20, wherein the preparatory dose of the P-gp inhibitor is about 0.01 mg to about 100 mg of said P-gp inhibitor.
  • Embodiment I-24 A combined oral preparation comprising about 1 mg to about 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2,4-dioxo- 1 ,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradiol equivalent; about 0.01 mg to about 5 mg of a progestin; and about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor; for simultaneous or sequential use in the treatment of one or more of uterine fibroids, endometriosis, aden
  • Embodiment I-25 A method for treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, the method comprising administering to the pre- menopausal woman, once daily, a combination comprising: about 1 mg to about 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)- N'-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.5 mg to about 2 mg of estradiol or a corresponding amount of estradio
  • Embodiment I-26 The combined oral preparation of embodiment I-24 or the method of embodiment I-25, wherein the pre-menopausal woman is a peri-menopausal woman.
  • Embodiment I-27 The combined oral preparation or the method of any one of embodiments I-24 to I-26, wherein after at least 4 consecutive weeks of administration of the combination, the pre-menopausal woman’s ovarian estrogen production is suppressed.
  • Embodiment I-28 The combined oral preparation or the method of any one of embodiments I-24 to I-27, wherein the pre-menopausal woman experiences a reduction in pain after beginning treatment compared to before treatment.
  • Embodiment I-29 The combined oral preparation or the method of any one of embodiments I-24 to I-28, wherein the pain is pelvic pain.
  • Embodiment I-30 The method of embodiment I-29, wherein the pelvic pain is dysmenorrhea.
  • Embodiment I-31 The combined oral preparation or the method of any one of embodiments I-24 to I-30, wherein the woman experiences an improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, constipation, anxiety, sleep disturbance, quality of life, activities of daily living, female sexual dysfunction, and depression.
  • symptoms which are selected from the group consisting of anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, constipation, anxiety, sleep disturbance, quality of life, activities of daily living, female sexual dysfunction, and depression.
  • Embodiment I-32 The combined oral preparation or the method of any one of embodiments I-24 to I-31, wherein the pre-menopausal woman experiences amenorrhea after beginning treatment compared to prior to treatment.
  • Embodiment I-33 The combined oral preparation or the method of any one of embodiments I-24 to I-32, wherein one or both of the number and size of the uterine fibroids are reduced after beginning treatment compared to one or both of the number and size of the uterine fibroids prior to treatment.
  • Embodiment I-34 The combined oral preparation or the method of any one of embodiments I-24 to I-33, wherein uterine volume is reduced after beginning treatment compared to prior to treatment.
  • Embodiment I-35 The combined oral preparation or the method of any one of embodiments I-24 to I-34, comprising about 2 mg to about 20 mg, or about 5 mg to about 20 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)- 2, 4-dioxo- 1,2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea.
  • Embodiment I-36 The combined oral preparation or the method of any of the preceding embodiments, wherein the P-gp inhibitor is selected from any of the P-gp inhibitors of Table 1.
  • Embodiment I-37 The combined oral preparation or the method of any of the preceding embodiments, wherein the P-gp inhibitor is erythromycin.
  • Embodiment I-38 The combined oral preparation or the method of any of the preceding embodiments, wherein the CYP3 A inhibitor is selected from any of the CYP3A inhibitors of Table 2.
  • Embodiment I-39 The combined oral preparation or the method of any of the preceding embodiments, wherein the CYP3A inhibitor is voriconazole.
  • Embodiment I-40 The combined oral preparation or the method of any of the preceding embodiments, wherein the combined oral preparation is administered as a single dosage form.
  • Embodiment I-41 The combined oral preparation or the method of any of the preceding embodiments, wherein the combined oral preparation comprises separate dosage forms that are co-administered.
  • Embodiment I-42 Use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea, or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor, for the manufacture of a medicament for the treatment of prostate cancer.
  • Embodiment I-43 Use of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent, a progestin, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor, for the manufacture of a medicament for the treatment of one or more of uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman.
  • Embodiment I-44 N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof for use in a method of treating prostate cancer, the method comprising: administering to the subject the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or
  • Embodiment I-45 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-44, the method comprising: administering to the subject about 1 mg to about 120 mg of the N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4- tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N' -methoxyurea, or
  • Embodiment I-46 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-44, the method comprising: administering to the subject once-daily for at least one day for a first treatment period, an oral load dose combination having about 1 mg to about 360 mg of the N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1, 2,3,4- tetrahydrothieno[2,3-d]
  • Embodiment I-47 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-44 or I-45, the method comprising: administering to the subject once daily a combined oral preparation comprising about 1 mg to about 120 mg of the N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl
  • Embodiment I-48 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-46, wherein the oral load dose combination further comprises about 0.01 mg to about 1000 mg of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3 A inhibitor.
  • Embodiment I-49 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-48, comprising about 20 mg of the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea
  • Embodiment I-50 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-48, wherein said administering comprises administration once daily of an oral load dose combination of from about 50 mg to about 100, about 50 to about 180, or from about 50 mg to about 240 mg of the N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3
  • Embodiment I-51 The N-(4-(1-(2,6- difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-48, wherein said administering comprises administration once daily of an oral maintenance dose combination of from about 15 mg to about 30 mg, from about 15 mg to about 40 mg, or from about 15 mg to about 80 mg of the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothien
  • Embodiment I-52 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-51, wherein the oral maintenance dose formulation administration begins on the day after administering the last dose of the oral load dose formulation.
  • Embodiment I-53 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-52, wherein the prostate cancer is hormone dependent prostate cancer.
  • Embodiment I-54 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3 -pyridazinyl)-2 ,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 -d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-53, wherein the prostate cancer is advanced prostate cancer.
  • Embodiment I-55 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-54, wherein the prostate cancer is metastatic, non-metastatic, locally advanced, advanced hormone sensitive, advanced castration resistant, or recurrent.
  • Embodiment I-56 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-55, wherein profound castration is achieved.
  • Embodiment I-57 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-56, wherein the profound castration is achieved within 24 to 48 hours after commencing administration and is maintained until the end of administration.
  • Embodiment I-58 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-57, wherein time to castration resistance is longer than in a subject receiving GnRH agonist therapy.
  • Embodiment I-59 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-47 to I-58, wherein said suspension period is up to 4 weeks, up to 12 weeks, up to 24 weeks, up to 36 weeks, or up to 52 weeks
  • Embodiment I-60 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-47 to I-58, wherein the suspension period is discontinued when the subject experiences return of symptoms of prostate cancer.
  • Embodiment I-61 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-60, wherein the combined oral preparation is administered for 12 consecutive weeks or greater, 24 consecutive weeks or greater, 48 consecutive weeks or greater, 52 consecutive weeks or greater, 72 consecutive weeks or greater, or 96 consecutive weeks or greater.
  • Embodiment I-62 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-45 to I-61, wherein said administering is preceded by at least 5 days of daily administration of a preparatory dose of a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor alone.
  • Embodiment I-63 N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, the method comprising: administering to the pre-menopausal woman the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-meth
  • Embodiment I-64 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-63, the method comprising: administering to the pre-menopausal woman, once daily, a combination comprising: about 1 mg to about 40 mg of the N-(4-(1-(2,6-difluorobenzyl)-5-
  • Embodiment I-65 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-64, wherein the pre-menopausal woman is a peri-menopausal woman.
  • Embodiment I-66 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-64 or I-65, wherein after at least 4 consecutive weeks of administration of the combination, the pre- menopausal woman’s ovarian estrogen production is suppressed.
  • Embodiment I-67 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-66, wherein the pre-menopausal woman experiences a reduction in pain after beginning treatment compared to before treatment.
  • Embodiment I-68 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-67, wherein the pain is pelvic pain.
  • Embodiment I-69 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to Embodiment I-68, wherein the pelvic pain is dysmenorrhea.
  • Embodiment I-70 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-69, wherein the woman experiences an improvement in one or more of the following symptoms, which are selected from the group consisting of anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, constipation, anxiety, sleep disturbance, quality of life, activities of daily living, female sexual dysfunction, and depression.
  • symptoms which are selected from the group consisting of anemia, irregular periods, spotting, inflammation, pain, fatigue, urinary obstruction, urinary frequency, incontinence, cons
  • Embodiment I-71 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-70, wherein the pre-menopausal woman experiences amenorrhea after beginning treatment compared to prior to treatment. [0154] Embodiment I-72.
  • Embodiment I-73 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-72, wherein uterine volume is reduced after beginning treatment compared to prior to treatment.
  • Embodiment I-74 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of Embodiments I-64 to I-73, the method comprising administering about 2 mg to about 20 mg or about 5 mg to about 20 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'
  • Embodiment I-75 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the P-gp inhibitor is selected from any of the P-gp inhibitors of Table 1.
  • Embodiment I-76 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the P-gp inhibitor is erythromycin.
  • Embodiment I-77 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the CYP3A inhibitor is selected from any of the CYP3A inhibitors of Table 2.
  • Embodiment I-78 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the C YP3 A inhibitor is voriconazole.
  • Embodiment I-79 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the combined oral preparation is administered as a single dosage form.
  • Embodiment I-80 The N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or pharmaceutically acceptable salt thereof for use according to any of the preceding embodiments, wherein the combined oral preparation comprises separate dosage forms that are co-administered.
  • Embodiment II- 1 A compound for use in a method of treating prostate cancer, wherein the compound is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof, a P-gp inhibitor, or a CYP3A inhibitor, the method comprising: administering to the subject N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phen
  • Embodiment II-2 A compound for use in a method of treating prostate cancer, wherein the compound is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethyIamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof, the method comprising: administering to the subject the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'
  • Embodiment II-3 A compound for use in a method of treating prostate cancer, wherein the compound is a P-gp inhibitor, the method comprising: administering to the subject N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- 3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1,2,3 ,4-tetrahydrothieno[2,3 -d]pyrimidin-6-yl)phenyl)- N' -methoxyurea or a pharmaceutically acceptable salt thereof, and a P-gp inhibitor or a combination of a P-gp inhibitor and a CYP3A inhibitor.
  • Embodiment II-4 A compound for use in a method of treating prostate cancer, wherein the compound is a CYP3 A inhibitor, the method comprising: administering to the subject N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)- 3-(6-methoxy-3-pyridazinyl)-2,4-dioxo- 1,2,3, 4-tetrahydrothieno[2, 3-d]pyrimidin-6-yl)phenyl)- N' -methoxyurea or a pharmaceutically acceptable salt thereof, and a combination of a P-gp inhibitor and a CYP3A. inhibitor.
  • Embodiments I-45 to I-80 relate to Embodiment I-44, those features of Embodiments I-45 to I-80 are applicable and hereby disclosed in combination with Embodiments II- 1 to II-4, mutatis mutandis.
  • Embodiment III- 1 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof, a P-gp inhibitor, a CYP3A inhibitor, estradiol, an estradiol equivalent, or a progestin, the method comprising: administering to the pre-menopausal woman
  • Embodiment III-2 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3- (6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'- methoxyurea or a pharmaceutically acceptable salt thereof, the method comprising: administering to the pre-menopausal woman the N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3
  • Embodiment III- 3 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is a P-gp inhibitor, the method comprising: administering to the pre-menopausal woman N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent, a progestin,
  • Embodiment III-4 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is a CYP3A inhibitor, the method comprising: administering to the pre-menopausal woman N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1, 2, 3, 4-tetrahydrothieno[2,3- d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent, a progestin, and a combination of a
  • Embodiment III-5 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is estradiol, the method comprising: administering to the pre-menopausal woman N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, an estradiol, a progestin, and a P-gp inhibitor or
  • Embodiment III-6 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is an estradiol equivalent, the method comprising: administering to the pre-menopausal woman N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, an estradiol equivalent, a progestin, and a P-g
  • Embodiment III-7 A compound for use in a method of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a pre-menopausal woman, wherein the compound is a progestin, the method comprising: administering to the pre-menopausal woman N-(4-(1-(2,6-difluorobenzyl)-5- ((dimethylamino)methyl)-3 -(6-methoxy-3 -pyridazinyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydrothieno[2,3 - d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof, estradiol or an estradiol equivalent, a progestin, and
  • Embodiments I-65 to I-80 relate to Embodiment I-64, those features are applicable and are hereby disclosed in combination with Embodiments III- 1 to III-7, mutatis mutandis.
  • Example 1 A Phase 1, Open-Label, Drug-Drug Interaction Study to Evaluate the Effects of Multiple Oral Doses of Fluconazole and Atorvastatin on the Pharmacokinetics of a Single Oral Dose of Compound 1 in Healthy Subjects
  • Diagnosis and Main Criteria for Inclusion Healthy male and female subjects between 18 and 55 years of age, inclusive, at the time of consent were enrolled. Subjects had a weight ⁇ 45 kg and body mass index between 18.0 and 30.0 kg/m2, inclusive, at screening, and all were nonsmokers.
  • Test Product, Dose and Mode of Administration, Batch Number Compound 1 was supplied as tablets of 40 mg dose strength. One lot of 40 mg Compound 1 tablets was administered in this study (lot #103074). Atorvastatin 80-mg tablets and fluconazole 200-mg tablets were supplied in the manufacturer’s original packaging. On dosing days, study drugs were administered orally in the morning with a full glass of water 30 minutes before breakfast after overnight fasting. One Compound 1 40-mg tablet was to be orally administered on Days 1 and 10. Fluconazole (200-mg tablet) or atorvastatin (80-mg tablet) was to be orally administered on Days 6 through 14.
  • Safety Assessments were assessed by the incidence, duration, and severity of adverse events (AEs) and serious adverse events (SAEs); by clinical laboratory assessments; by periodic physical examinations; by changes in vital signs including oral temperature, heart rate, and diastolic and systolic blood pressure; and by 12-lead electrocardiograms (ECGs).
  • AEs adverse events
  • SAEs serious adverse events
  • ECGs 12-lead electrocardiograms
  • Safety data analyses consisting of data summaries for clinical and laboratory parameters as well as AEs, were conducted on all subjects who received at least 1 dose of study drugs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 17.0). The number and percentage of subjects experiencing 1 or more AEs were summarized by the relationship to Compound 1 , fluconazole, and atorvastatin dose administration as well as by severity based on National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, effective date 14 June 2010.
  • TEAEs treatment-emergent AEs
  • Day 22 ⁇ 3 days The most commonly reported TEAEs, reported for at least 10% of all subjects, were summarized.
  • TEAEs were tabulated by MedDRA System Organ Class and Preferred Term.
  • Laboratory parameters were summarized using descriptive statistics, by post-treatment shifts relative to baseline, and data listings of clinically significant abnormalities.
  • Vital signs and ECG data were summarized by changes from baseline values using descriptive statistics.
  • PK parameters including but not limited to: observed maximum plasma concentration (Cmax), single-dose first time of occurrence of maximum (peak) concentration, area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration, area under the plasma concentration versus time curve from time 0 to infinity (AUCO-inf), terminal disposition half-life, apparent terminal phase volume of distribution, apparent total body clearance, amount of Compound 1 excreted in the urine, expressed as a percent of administered dose, and renal clearance.
  • Descriptive statistics included number, arithmetic mean, standard deviation (SD), coefficient of variation (CV%), geometric mean and C V%, minimum, maximum, and median.
  • Individual plasma and urine Compound 1 concentration-time data were listed by treatment, study day, subject identifier (ID), and nominal/ actual time and summarized descriptively by treatment, study day, and nominal time for all subjects in the safety population.
  • individual plasma and urine PK parameters for Compound 1 were listed by treatment, subject ID, and study day and summarized descriptively by treatment and study day for all subjects in the PK-evaluable population.
  • individual trough plasma concentrations of fluconazole and atorvastatin (and active metabolites) were listed by subject ID, study day, and nominal/ actual time and summarized descriptively by nominal study day.
  • Disposition A total of 40 subjects were enrolled and received drug in this study; 20 subjects were assigned to each treatment arm. One subject in the atorvastatin arm withdrew consent on Day 3 (due to a personal emergency); hence, 39 subjects completed the study as planned.
  • Demographic and Baseline Characteristics The mean age (SD) for all subjects was 38.8 (9.72) years, ranging from 21 to 55 years of age. An equal number of men and women were enrolled in each treatment arm (10 subjects [50%] each). Subjects were primarily white (34 subjects [85%]) and Hispanic or Latino (31 subjects [78%]). Demographics were similar between Arm 1 and Arm 2.
  • TEAEs Treatment-emergent Adverse Events: TEAEs were similar for Compound 1 alone and dosed concomitantly with atorvastatin or fluconazole. The most commonly reported TEAEs, occurring in > 5% of subjects in the fluconazole or atorvastatin arms, respectively, were pruritus (0 [0%], 3 [15%]), rash papular (0 [0%], 2 [10%]), erythematous rash (0 [0%]; 3 [15%]), and arthropod bite (2 [10%], 1 [5%]). Three subjects experienced 4 events that were considered to be related to Compound 1. One subject reported the events of somnolence and dizziness and 2 subjects reported events of hypoaesthesia that were considered by the investigator to be related to Compound 1. All 4 events were Grade 1 in severity and had no associated objective or physical examination findings.
  • Example 2 A 2-Part, Open-Label, Fixed-Sequence, 2-Period Crossover Study to Assess the Effects of Voriconazole on the Pharmacokinetics of Compound 1 in Healthy Adult Men and Women
  • a two-part, open-label, fixed-sequence, two-period crossover drug interaction study was conducted to assess the potential effects of voriconazole on the pharmacokinetics of Compound 1 in healthy, adult men and women.
  • Each study part consisted of two sequential treatment periods (Treatment Period 1 and Treatment Period 2) in which study participants received study treatments in a fixed (single)-sequence, crossover manner. There was a 10-day washout interval between study drug administration on Day 1 of Treatment Period 1 and Treatment Period 2.
  • Each study participant was screened for study eligibility at a Screening Visit within 30 days prior to study drug administration on Day 1 of Treatment Period 1.
  • Diagnosis and Main Criteria for Inclusion and Exclusion Healthy, non-smoking, men and women, 18 to 65 years of age, inclusive, with a body mass index (BMI) of 18.5 to 30.0 kg/m 2 , inclusive.
  • BMI body mass index
  • Part 1 The majority of participants were women (81.3%), White (93.8%) and were of Hispanic or Latino ethnicity (87.5%). The mean age was 41.3 years and ranged from 20 to 56 years. The mean BMI was 27.21 kg/m2 and all study participants had a BMI of ⁇ 30 kg/m2. Part 2: All participants were men, with the majority being White (62.5%) and of Hispanic or Latino ethnicity (75.0%). The mean age was 43.4 years and ranged from 32 to 56 years. The mean BMI was 27.74 kg/m2 and all study participants had a BMI of ⁇ 30 kg/m2.
  • Exposure Part 1 : All 16 participants received a single 40-mg dose of Compound 1 alone in Treatment Period 1. Two participants prematurely discontinued from the study prior to Treatment Period 2 and fourteen participants received at least one dose of voriconazole in Treatment Period 2. Another participant prematurely discontinued on Day 4 of Treatment Period 2 after receiving 7 doses of voriconazole.
  • Part 2 All 16 participants received a single 120-mg dose of Compound 1 alone in Treatment Period 1 of the study.
  • Part 2 The AUC0- ⁇ , AUC0-t, and Cmax of Compound 1 were prespecified as primary pharmacokinetic parameters upon which the effects of voriconazole were to be based. After co-administration of Compound 1 120 mg and voriconazole, the AUCO- oo, AUC0-t of Compound 1 were increased by approximately 1.12- and 1.10-fold, respectively (GMRs [co-administration ⁇ Compound 1 + voriconazole ⁇ /Compound 1 alone] and 90% CIs for the AUC0- ⁇ AUC0-t were 1.1181 [0.6806, 1.8371], 1.0980 [0.6645, 1.8143], However, the Cmax of Compound 1 was decreased by 18% after co-administration of Compound 1 120 mg and voriconazole (GMR [co-administration ⁇ Compound 1 + voriconazole ⁇ /Compound 1 alone] and 90% CI for the Cmax was 0.8185 [0.4261, 1.5724]).
  • Part 1 (Compound 1 40 mg): After co-administration of Compound 1 with voriconazole, a strong CYP3A4 inhibitor, a modest and variable increase in exposure to Compound 1, which were considered not to be clinically meaningfill, was observed.
  • the total exposure (AUC0- ⁇ and AUC0-t) and maximum concentration (Cmax) of Compound 1 were increased by 1.5-, 1.5- and 1 ,2-fold, respectively, after co-administration of Compound 1 40 mg and voriconazole (GMR [co-administration ⁇ Compound 1 40 mg + voriconazole ⁇ /Compound 1 40 mg alone] and 90% CI for the AUC0- ⁇ , AUC0-t, and Cmax of Compound 1 are 1.5115 [1.2458, 1.8339], 1.4876 [1.2161, 1.8197], and 1.2074 [0.9193, 1.5857], respectively).
  • Part 2 (Compound 1 120 mg): After co-administration of Compound 1 with voriconazole, a strong CYP3 A4 inhibitor, small and considerably variable changes in exposure to Compound 1, which were considered not to be clinically meaningful, were observed.
  • the total exposure (AUC0- ⁇ and AUC0-t) of Compound 1 was increased by 1.2- and 1.1-fold, respectively, whereas maximum concentration (Cmax) of Compound 1 was decreased by 18%, after co-administration of Compound 1 120 mg and voriconazole (GMR [co-administration ⁇ Compound 1 + voriconazole ⁇ /Compound 1 alone] and 90% CI for the AUC0- ⁇ , AUC0-t, and Cmax of Compound 1 are 1.1181 [0.6806, 1.8371], 1.0980 [0.6645, 1.8143], and 0.8185 [0.4261, 1.5724], respectively.
  • Example 3 A Study to Determine the Effect of Rifampin on the Pharmacokinetics of Compound 1 in Healthy Adult Subjects
  • Table 4 shows the study design and results for the effect of rifampin on the pharmacokinetics of Compound 1 in healthy adult subjects.
  • Table 4 Study design and results for the effect of rifampin on the pharmacokinetics of Compound 1 in healthy adult subjects.
  • Example 4 A Phase 1, Open-label, Drug-drug Interaction Study to Evaluate the Effects of Multiple Oral Doses of Erythromycin on the Pharmacokinetics of a Single Oral Dose of Compound 1 in Healthy Adult Male and Female Subjects
  • Erythromycin was given orally at 300 mg 4 times daily (30 minutes before each meal and before bedtime) for 10 days from Day 10 to Day 19. Subjects simultaneously received 300 mg of erythromycin and 20 mg of Compound 1 at 30 minutes before breakfast on Day 15. The evaluation period lasted for 27 days after the start of study drug administration.
  • Table 5 shows an overview of the study design. Table 5: Overview of the study design to evaluate the effects of erythromycin on PK and Safety and tolerability of a single dose of Compound 1 [0215] Number of Subjects: Planned: 20 subjects (10 males and 10 females). Screened: 48 subjects. Enrolled in the Treatment Period: 20 subjects (10 males and 10 females).
  • Diagnosis and Main Criteria for Inclusion Healthy Japanese male and female subjects, aged 20 to 45 years, with a body weight of at least 40 kg for female subjects who had at least 3 regular menstrual cycles immediately before informed consent, and 50 kg for male subjects, and a body mass index (BMI) between 18.5 and 25.0 kg/m2.
  • BMI body mass index
  • Duration of Treatment Following a 28-day screening period, subjects were confined in the investigational site for 7 days from Day -1 to Day 6, for administration of Compound 1 alone, and again for 12 days from Day 9 to Day 20, for combination treatment with Compound 1 and erythromycin. Compound 1 was administered on Day 1 and Day 15, and erythromycin for 10 days from Day 10 to Day 19. A follow-up visit was set on Day 27.
  • Test Product, Dose, and Mode of Administration Compound 1 (20 mg tablet, 20 mg/day; oral; Lot Z6548032); Erythromycin (100 mg tablet, 1200 mg/day - 300 mg each 4 times daily; oral; Lot Z654D011).
  • Statistical Methods - Plasma Concentration The plasma concentrations of Compound 1 was summarized by each administration condition (Compound 1 alone, and in combination with erythromycin), over each scheduled sampling interval using descriptive statistics. Plot of time profiles for Compound 1 plasma concentrations (individual data, and for arithmetic means with standard deviation (SD) data for each) were generated by each administration condition.
  • the pharmacokinetic (PK) parameters [excluding AUMC(0-tlqc) and AUMC(0-inf) ] were summarized by each period using descriptive statistics.
  • CIs Two-sided confidence intervals (CIs) (confidence coefficient level; 90% and 95%) of the ratio between the administration condition (combination / alone) were calculated, based on analysis of variance (ANOVA) with natural log- transformed AUC(0-inf), AUC(0-120), AUC(--tlqc), and Cmax of Compound 1 as dependent variables and administration condition as fixed effects.
  • ANOVA analysis of variance
  • the above analysis was also performed without log-transformation, for reference.
  • the log-transformed Tmax, MRT, and z were also to be evaluated in the same way, as required.
  • some analyses relating to gender were performed.
  • TEAEs treatment-emergent adverse events
  • SOC System Organ Class
  • PT Preferred Term
  • TEAEs were presented in descending order of event frequency. The incidence of serious TEAEs was to be calculated. If events under the same SOC were recorded more than once in the same subject, the subject was to be counted as 1 subject in the SOC. If events under the same PT were recorded more than once in the same subject, the subject was to be counted as 1 subject in the PT. If events under the same PT or SOC were recorded more than once with different intensities, the subject was to be counted as 1 subject in the most severe category. TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA).
  • MedDRA Medical Dictionary for Regulatory Activities
  • Baseline Demographics and Other Baseline Characteristics A total of 48 subjects were screened for this study. Of these, 20 subjects received the study drug.
  • the age (mean ⁇ SD) was 27.8 ⁇ 3.88 years in the male subjects, 24.4 ⁇ 3.44 years in the female subjects and 26.1 ⁇ 3.97 years in the combined male/female subjects;
  • the height was 170.1 ⁇ 3.54 cm, 157.5 ⁇ 4.33 cm and 163.8 ⁇ 7.52 cm, respectively;
  • the weight was 65.34 ⁇ 6.014 kg, 50.25 ⁇ 6.470 kg and57.80 ⁇ 9.843 kg, respectively;
  • the BMI was 22.49 ⁇ 1.488 kg/m2, 20.17 ⁇ 1.947 kg/m2 and 21.33 ⁇ 2.064 kg/m2, respectively, showing no significant differences between male and female subjects except for height and weight.
  • Plasma concentrations of unchanged Compound 1 In the PK analysis set, the time profiles of mean plasma concentrations of unchanged Compound 1 after administration of Compound 1 20 mg alone (the Compound 1 -alone period) and administration of Compound 1 20 mg in a steady state of erythromycin (1200 mg/day) (the combination period), and the results over the course of 120 hours are shown in in FIG. 1A.
  • FIG. IB shows the same data over the period of 0-24 hours.
  • Table 6 shows descriptive statistics for PK parameters of Compound 1.
  • the plasma concentrations of unchanged Compound 1 immediately following the administration was higher in the combination period than in the Compound 1 -alone period.
  • the Tmax of each subject was reached within 2 hours in both treatment periods.
  • Compound 1 rapidly decreased for the first 4 to 6 hours after reaching Tmax and thereafter gradually decreased in each treatment period.
  • the Tl/2 (mean ⁇ SD) was 45.54 ⁇ 13.118 hours in the Compound 1- alone period and 44.36 ⁇ 5.0034 hours in the combination period, showing almost no difference.
  • the Cmax (mean ⁇ SD) was 9.191 ⁇ 8.6165 ng/mL in the Compound 1-alone period and 44.48 ⁇ 19.828 ng/mL in the combination period, and the AUC (0-inf) was 45.03 ⁇ 25.845 ng*hr/mL in the Compound 1-alone period and 253.2 ⁇ 63.242 ng*hr/mL in the combination period.
  • the Cmax and AUC(0-inf) were higher in the combination period than in the Compound 1-alone period.
  • Table 7 The ratio of PK parameters of Compound 1 between the administration condition (combination/alone)
  • Urinary excretion ratio of unchanged Compound 1 The cumulative urinary excretion ratio (mean ⁇ SD) of Compound 1 up to 120 hours after administration was 1.571 ⁇ 0.9868% of dose in the Compound 1 -alone period and 8.466 ⁇ 1.8392% of dose in the combination period.
  • the renal clearance (CLr) was 7.056 ⁇ 1.2579 L/hr in the Compound 1 -alone period and 6.803 ⁇ 0.95296 L/hr in the combination period, showing almost no differences between treatment periods.
  • Plasma concentrations of erythromycin The plasma concentrations of erythromycin (mean ⁇ SD) on each administration day were in the range of 117.9 ⁇ 76.630 to 262.4 ⁇ 217.52 ng/mL. All the subjects maintained nearly constant plasma concentrations of erythromycin throughout Day 13 to 19.
  • Safety Results In the safety analysis set, the incidence of TEAEs was 35% (7/20 subjects, 7 events) in all of the subjects. The incidence of TEAEs of each treatment period was 5% (1/20 subjects, 1 event) in the Compound 1 -alone period, 0% (0/20 subjects, 0 events) in the erythromycin-alone period, and 30% (6/20 subjects, 6 events) in the combination period. All the TEAEs were reported only in the female subjects (70%, 7/10 subjects, 7events). The details were menstruation irregular (50%, 5/10 female subjects), metrorrhagia (10%, 1/10 female subjects), and diarrhoea (10%, 1/10 female subjects).
  • TEAEs were considered related to the study drug, mild in severity, and recovered without any treatment. No clinically significant changes in clinical laboratory tests (serum chemistry, hematology, and urinalysis), vital signs, weight, and ECG results were observed in any subjects.
  • FIG. 5 A summary of dosing schedules of the drug interaction studies described in Examples 1-4 is shown in FIG. 5. Labels indicate on which days relugolix was co-administered.
  • Example 5 A Study to Determine the Effect of P-gp Transporters on Nonlinear PK Properties of Compound 1
  • Test and Control Articles Compound 1 (Lot M285-011, purity: 99.9%) was the test article used in this study.
  • the vehicle used for reconstitution of the test article formulations was 0.5% HPMC/0.6% citric acid and a 1 : 1 :4:4 mixture (by volume) of ethanol;
  • DMA N, N-dimethylacetamide
  • polyethylene glycol 400 polyethylene glycol 400
  • sterile water sterile water
  • Test System The animals used in this study are described in All doses, plasma concentrations, and derived PK parameters are presented as the free base of Compound 1.
  • Male Sprague-Dawley rats were administered elacridar hydrochloride (0.3 and 1.0 mg/kg) or 0.5% hydroxypropyl methylcellulose (HPMC)/1% Tween® 80 (MP Biomedicals [Solon, OH, USA]) PO once. After 30 minutes, 1.0-mg/kg Compound 1 was administered as a single PO or IV dose.
  • the experimental design mimicked a Latin square.
  • Compound 1 IV administration was via a jugular vein catheter over 10 to 20 seconds, followed by a 0.3-mL flush of 0.9% sterile saline.
  • Whole blood samples were collected from all animals 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours postdose.
  • n 3 for all dose groups.
  • a Pretreatment was dosed PO.
  • b Values are presented as the mean.
  • c Calculated as the mean AUC24 with pretreatment of elacridar/mean AUC 24 without pretreatment of elacridar.
  • d Calculated as the mean Cmax with pretreatment of elacridar/mean Cmax without pretreatment of elacridar.
  • Table 10 Summary of Key Pharmacokinetic Parameters in Plasma After Oral and Intravenous Administration of 1.0-mg/kg Compound 1 to Male Sprague-Dawley Rat
  • n 3. “Calculated as the mean AUC 24 with pretreatment of elacridar / mean AUC 24 without pretreatment of elacridar. bCalculated as the mean C max with pretreatment of elacridar / mean C max without pretreatment of elacridar. c Dosed orally (PO). d Control was dosed 0.5% HPMC (hydroxypropyl methylcellulose)/1% Tween ® 80 (MP Biomedicals [Solon, OH, USA]). Dosed orally (PO).
  • the apparent permeability coefficient (P app ) value of [ 14 C]Compound 1 from the apical to the basal side was 0.513X10 -6 cm/sec, and that from the basal to the apical side was 8.43x 10 -6 cm/sec.
  • the P app ratio was 16.4.
  • the Papp value of [ 14 C]Compound 1, after incubation with 30 ⁇ mol/L quinidine, was 2.34x10 -6 cm/sec from the apical to the basal side, and that from the basal to the apical side was 5.06x10 -6 cm/sec.
  • the P app ratio, after incubation with 30 ⁇ mol/L quinidine, was 2.2.
  • the P app value of [ 14 C]Compound 1 after incubation with 10 ⁇ mol/L GF120918, was 2.75x10 -6 cm/sec from the apical to the basal side, and that from the basal to the apical side was 1.98x 10 -6 cm/sec.
  • the P app value of [ 14 C]Compound 1, after incubation with 1 ⁇ mol/L KO143 was 0.465x10 -6 cm/sec from the apical to the basal side, and that from the basal to the apical side was 7.02x 10 -6 cm/sec.
  • the P app ratio, after incubation with 1 ⁇ mol/L KO 143 was 15.1.
  • FIG. 2 shows the Transcellular transport of [3H] digoxin (3 ⁇ mol/L), [3H] estrone 3- sulfate (0.1 ⁇ mol/L), [14C]antipyrine (10 ⁇ mol/L) and [14C]mannitol (10 pmol/L) across Caco- 2 cell monolayers.
  • Each bar (Papp value) represents the mean ⁇ SD of three samples.
  • Each point (Papp ratio) was calculated using the mean Papp value of three samples.
  • Caco-2 cells were incubated at 37°C.
  • FIG. 3 shows the transcellular transported amount of [14C] Compound 1 (3 pmol/L) across Caco-2 cell monolayers. Each value represents the mean ⁇ SD of three samples. Caco-2 cells were incubated at 37°C Example 7: A Study to Determine the Michaelis-Menten constant (K m ) and maximal efflux rate (V max ) and to evaluate the potential interactions of Compound 1 with the efflux transporter P-gp (encoded by MDR1) in Caco-2 cells
  • Example 6 showed Compound 1 to be a substrate for P-gp using the Caco-2 cell model.
  • the permeation clearance of Compound 1 by P-gp was assessed in the basolateral- to-apical (B-to-A) direction in Caco-2 cells using multiple concentrations of Compound 1 labeled with radioactive carbon (14C) in the absence or presence of the P-gp inhibitor LY335979.
  • the Km and Vmax ofCompound 1 were 66.5 ⁇ M and 3047 pmol/hr, respectively.
  • the P-gp-mediated membrane permeation clearance of Compound 1 was 93.9%.
  • Test and Control Articles Test articles Compound 1 (Lot M285-011) and
  • Compound 1 (Lot A- 131116) were provided by Takeda Pharmaceutical Company Limited (Fujisawa, Kanagawa, Japan).
  • P-gp inhibitor LY335979 (Lot MP -2014-003) was synthesized by personnel at Millennium.
  • Control P-gp substrate digoxin (Lot SLBF 1625V) was purchased from Sigma-Aldrich Chemical. Company (St Louis, MO, USA).
  • Digoxin labeled with 3H (Lot 1817185) was purchased from Moravek Biochemicals (Brea, CA, USA).
  • Caco-2 cell was obtained from American Type Culture Collection (ATCC) (Manassas, VA, USA).
  • the stock cells were cultured in 162-cm 2 tissue culture T-flasks for subsequent use.
  • Table 11 shows the kinetic parameters of Compound 1 and digoxin with P-gp in Caco-2 cells, whilel Table 12 shows the transport rates of digoxin in Caco-2 cells.
  • V max maximal efflux rate.
  • a K m and V max were calculated with XL-Fit Excel Add-in Version 5.3.1.3 (ID Business Solutions Ltd [Cambridge, MA, USA]).
  • b Membrane permeation clearance ratio CL(P-gp)/(CL[P-gp] + CL[passive]).
  • a Data expressed as mean ⁇ standard error of the mean [SEM] (n 3).
  • b LY335979 is an inhibitor of P-gp, and was tested at 10 ⁇ M.
  • c n 2. Data from the third well at this concentration were excluded because of the low transepithelial electrical resistance (TEER) at the end of the assay
  • FIG. 4A shows the Compound 1 flux in Caco-2 cells.
  • FIG. 4B shows the digoxin flux in Caco-2 cells.
  • Example 8 Summary of open-label clinical trials of Example 1-4

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Abstract

La présente invention concerne des préparations orales combinées de N-(4-(1-(2,6-difluorobenzyl)-5-((diméthylamino)méthyl)-3-(6-méthoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidin-6-yl)phényl)-N'-méthoxyurée (Composé 1) et d'un inhibiteur de P-gp ou une combinaison d'un inhibiteur de P-gp et d'un inhibiteur de CYP3A, et des méthodes de traitement et des utilisations pour le cancer de la prostate, les fibromes utérins, l'endométriose, l'adénomyose, les saignements menstruels abondants ou la douleur associée aux fibromes utérins, à l'endométriose et à l'adénomyose comprenant leur administration.
PCT/EP2021/081304 2020-11-11 2021-11-10 Méthodes d'administration du rélugolix Ceased WO2022101303A1 (fr)

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