111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US009943526B2
`
`c12) United States Patent
`Belanoff et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,943,526 B2
`Apr. 17, 2018
`
`(54) OPTIMIZING MIFEPRISTONE LEVELS FOR
`CUSHING'S PATIENTS
`
`201110166115 A1
`201110294771 A1
`2013/0131030 A1
`
`7/2011 Belanoff
`12/2011 Belanoff
`5/2013 Belanoff
`
`(71) Applicant: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`
`(72)
`
`Inventors: Joseph Belanoff, Woodside, CA (US);
`Coleman Gross, Menlo Park, CA (US)
`
`(73) Assignee: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 15/133,791
`
`(22) Filed:
`
`Apr. 20, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0310507 Al
`
`Oct. 27, 2016
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 62/150,757, filed on Apr.
`21, 2015.
`
`(51)
`
`(52)
`
`(58)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311122
`A61K 311135
`A61K 311136
`A61K 311567
`G01N 33194
`U.S. Cl.
`CPC .......... A61K 311567 (2013.01); A61K 311122
`(2013.01); A61K 311135 (2013.01); A61K
`311136 (2013.01); G01N 33194 (2013.01);
`GOJN 2800/048 (2013.01); GOJN 2800/52
`(2013.01)
`
`Field of Classification Search
`CPC .. A61K 31/567; A61K 31/122; A61K 31/135;
`A61K 31/136
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,150,349 A
`6,369,046 B1
`6,620,802 B1
`6,680,310 B2
`6,964,953 B2
`7,163,934 B2
`7,326,697 B2
`7,361,646 B2
`7,402,578 B2
`8,097,606 B2
`8,598,149 B2
`8,921,348 B2
`2004/0132703 A1
`2004/0229855 A1
`2006/0063748 A1
`2007/0238779 A1
`2010/0179115 A1
`201110144072 A1
`
`1112000 Schatzberg et a!.
`4/2002 Schatzberg et a!.
`9/2003 Schatzberg et a!.
`112004 Belanoff et a!.
`11/2005 Belanoff
`112007 Belanoff
`2/2008 Schatzberg et a!.
`4/2008 Belanoff
`7/2008 Belanoff
`112012 Belanoff
`12/2013 Belanoff
`12/2014 Belanoff
`7/2004 Belanoff
`11/2004 Belanoff
`3/2006 Belanoff
`10/2007 Roberts et al.
`7/2010 Belanoff
`6/20 11 Belanoff
`
`FOREIGN PATENT DOCUMENTS
`
`wo
`
`2009050136 A2
`
`4/2009
`
`OTHER PUBLICATIONS
`
`Chu et al., "Successful Long-Term Treatment of Refractory
`Cushing's Disease with High-Dose Mifepristone (RU 486)", The
`Journal of Clinical Endocrinology & Metabolism 86(8):3568-3573,
`Aug. 2001.
`Gross et a!., Mifepristone Reduces Weight Gain and Improves
`Metabolic Abnormalities Associated With Risperidone Treatment in
`Normal Men. Obesity vol. 18, No. 12, Nov. 12/Dec. 2010; Pub(cid:173)
`lished online Mar. 25, 2010.
`(http:/ /www.nlm.nih.gov/
`Medical Encyclopedia of Medline
`medlineplus/ency/article/003430.htm), 4 pages, Oct. 2005.
`Sarkar, "Mifepristone: bioavailability, pharmacokinetics and use(cid:173)
`effectiveness," European Jourhal of Obstetrics and Gyhecology and
`Reproductive Biology, vol. 101, pp. 113-120 (2002).
`Fleseriu, et al., "Mifepristone, a Glucocorticoid Receptor Antago(cid:173)
`nist, Produced Clinical and Metabolic Benefits in Patients with
`Cushing's Syndrome" J Clin Endroclinol Metab 97(6):2039-2049
`(2012).
`Lee et a!., Office of Clinical Pharmacology Review NDA 20687
`(Addendum, Korlym™, Mifepristone) (2012).
`Tsigos, "Differential Diagnosis and Management of Cushing's
`Syndrome", Ann. Rev. Med. vol. 47, pp. 443-461 (1996).
`"Food-Effect Bioavailability and Fed Bioequivalence Studies"
`Guidance for Industry, U.S. Department of Health and Human
`Services, Food and Drug Administration, Center for Drug Evalua(cid:173)
`tion and Research, Dec. 2002, pp. 1-12. https:/ /www.fda.gov/down(cid:173)
`loads/ drugs/ guidancecomplianceregulatoryinforrmtation/ guid(cid:173)
`ances/ucm070241.pdf.
`The Biopharmaceutics Classification System (BCS) Guidance
`https:/ /www.fda.gov/ AboutFDA/CentersOffices/Of(cid:173)
`ficeofMedicalProductsandTobacco/CDER/ucm128219.htm.
`The New Drug Application (NDA) BA and BE Draft Guidance
`(Guidance for Industry. Bioavailability and Bioequivalence Studies
`Submitted in NDAs or INDs---General Considerations. U.S.
`Department of Health and Human Services, Food and Drug Admin(cid:173)
`istration, Center
`for Drug Evaluation
`and Research,
`Biopharmaceutics, Mar. 2014) https://www.fda.gov/downloads/
`drugs/ gui dancecomplianceregulatoryinformation/ guidances/
`ucm389370.pdf.
`
`(Continued)
`
`Primary Examiner- Yang S. Chong
`(74) Attorney, Agent, or Firm- Kilpatrick Townsend &
`Stockton LLP
`
`ABSTRACT
`(57)
`The present invention provides a method for optimizing
`levels of mifepristone in a patient suffering from Cushing's
`syndrome. The method comprises the steps of treating the
`patient with seven or more daily doses of mifepristone over
`a period of seven or more days; testing the serum levels of
`the patient to determine whether the blood levels of mife(cid:173)
`pristone are greater than 1631 ng/mL; and adjusting the
`daily dose of the patient to achieve mifepristone blood levels
`greater than 1631 ng/mL.
`
`9 Claims, No Drawings
`
`1
`
`TEVA1039
`
`

`

`US 9,943,526 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Hofsaess et a!., "Establishing the BCS Classification of APis
`Recently Added to the WHO Essential Medicines List," Poster
`Presentation at the 2015 AAPS Annual Meeting and Exposition;
`Oct. 1-3, 2015, St. Louis, MO, Poster T2064.
`Winstanley eta!., "The effects of food on drug bioavailability" Br.
`J. clin. Pharmac. (1989) 28:621-628.
`
`2
`
`

`

`US 9,943,526 B2
`
`2
`greater than 1631 ng/mL. The daily dose of the patient is
`then adjusted in order to achieve mifepristone blood levels
`of greater than 1631 ng/mL.
`Previous methods of optimizing mifepristone levels are
`5 known for patients suffering from mental disorders. But the
`earlier methods describe a minimum mifepristone blood
`level of only 1300 ng/mL. While patients with Cushing's
`syndrome are known to have higher cortisol levels, it is
`surprising that higher mifepristone blood level of 1631
`10 ng/mL would be necessary to achieve optimal efficacy in
`treating Cushing's syndrome.
`II. Definitions
`"Mifepristone" refers to a compound having the following
`15 structure:
`
`1
`OPTIMIZING MIFEPRISTONE LEVELS FOR
`CUSHING'S PATIENTS
`
`CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
`This application claims priority to U.S. Provisional Appli(cid:173)
`cation No. 62/150,757, filed Apr. 21, 2015, which is incor(cid:173)
`porated in its entirety herein for all purposes.
`
`BACKGROUND OF THE INVENTION
`
`It has been reported previously that administration of the
`same dose of mifepristone can produce widely varying
`blood serum levels in different patients. The varied blood
`serum levels can result in some patients not receiving an
`efficacious dose of mifepristone. For patients suffering from
`a mental disorder, the blood serum levels need to be main(cid:173)
`tained at about 1300 ng/mL. For patients suffering from 20
`Cushing's syndrome, it was surprisingly discovered that
`blood serum levels need to be maintained at a level of at least
`about 1631 ng/mL for a therapeutic response. Thus, a
`method for ensuring that the blood serum levels of mife(cid:173)
`pristone remain in an efficacious and safe range is needed for 25
`patients suffering from Cushing's syndrome.
`
`BRIEF SUMMARY OF THE INVENTION
`
`0
`
`In one embodiment, the present invention provides a
`method for improving efficacy of mifepristone treatment in
`a patient suffering from Cushing's syndrome. The method
`includes treating the patient with seven or more daily doses
`of mifepristone over a period of seven or more days; testing
`the serum levels of the patient to determine whether the
`blood levels of mifepristone are greater than 1631 ng/mL;
`and adjusting the daily dose of the patient to achieve
`mifepristone blood levels greater than 1631 ng/mL. The
`patient of the present invention is not already suffering from
`a condition indicated for treatment with mifepristone. Thus,
`the method thereby improves the efficacy of mifepristone
`treatment for patients suffering from Cushing's syndrome
`for the patient suffering from Cushing's syndrome.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`I. Introduction
`Administration of the same dose of mifepristone can
`produce widely varying mifepristone blood serum levels in
`different patients. For the same dose, the blood serum levels
`can differ by as much as 800% from one patient to another.
`For those patients with lower blood serum levels, the effec(cid:173)
`tiveness of mifepristone treatment can suffer significantly.
`The present invention provides a method for optimizing the
`blood serum levels of mifepristone so that the blood serum
`levels remain in an efficacious range and the patient receives
`the necessary treatment.
`The method of the present invention optimizes blood
`serum levels of mifepristone in a patient suffering from
`Cushing's syndrome by first treating the patient with mife(cid:173)
`pristone. The treatment can be for any appropriate period of
`time, such as seven or more daily doses over a period of
`seven or more days. Following treatment for an appropriate
`period of time, the serum levels of the patient are tested to
`determine whether the blood levels of mifepristone are
`
`The term mifepristone also refers to a family of compo-
`30 sitions also known as: RU486 or RU38.486; 17 -beta-hy(cid:173)
`droxy-11-beta-( 4-dimethyl-aminophenyl)-17 -alpha-(1-pro-
`11-beta-
`pynyl)-estra-4,9-dien-3-one );
`( 4dimethylaminophenyl)-17 -beta-hydroxy-17 -alpha-(1-
`35 propynyl)-estra-4,9-dien-3-one );
`llB[p-(Dimethylamino)
`phenyl]-17B-hydroxy-17 -(1-propynyl)-estra-4,9-dien-3-
`liB-( 4-dimethyl-aminophenyl)-17B-hydroxy-17 A(cid:173)
`one;
`(prop-1-ynyl)-estra-4,9-dien-3-one; 17B-hydroxy-11B-( 4-
`dimethylaminophenyl-1 )-17 A-(propynyl-1 )-estra-4,9-
`40 diene-3-one; 17B-hydroxy-11B-( 4-dimethylaminophenyl-
`1)-17 A-(propynyl-1)-E; (11B,17B)-11-[ 4-dimethylamino)(cid:173)
`phenyl]-17 -hydroxy-17 -(1-propynyl)estra-4,9-dien-3-one;
`and
`liB-[ 4-(N,N-dimethylamino) phenyl]-17 A-(prop-1-
`ynyl)-D-4,9-estradiene-17B-ol-3-one. Salts, hydrates and
`45 prodrug forms of mifepristone are also useful in the formu(cid:173)
`lations of the present invention.
`Mifepristone and its analogs bind to the glucocorticoid
`receptor (GR), typically with high affinity, and inhibit the
`biological effects initiated/mediated by the binding of any
`50 cortisol or cortisol analogue to the GR. As such, mifepris(cid:173)
`tone has been used to treat conditions associated with
`elevated cortisol levels including, for example, hyperadre(cid:173)
`nocorticism, also known as Cushing's syndrome (Chrousos,
`pp 273-284, In: Baulieu, ed. The Antiprogestin Steroid RU
`55 486 and Human Fertility Control. Plenum Press, New York
`(1989), Sartor (1996) Clin. Obstetrics and Gynecol. 39:506-
`510). Patients with some forms of psychiatric illnesses can
`be responsive to treatments which block the effect of corti(cid:173)
`sol, as by administering GR antagonists (Van Look (1995)
`60 Human Reproduction Update 1:19-34). In one study, a
`patient with depression associated with Cushing's Syn(cid:173)
`drome was responsive to a high dose, up to 1400 mg per day,
`of mifepristone (Nieman (1985) J. Clin Endocrinol. Metab.
`61:536). Due to its antiprogestogenic activity, mifepristone
`65 has also been employed in emergency contraception, medi(cid:173)
`cal abortion, and treatment of uterine fibroids and menin(cid:173)
`gioma (Healy (2009) Australian Prescriber 32:152-154).
`
`3
`
`

`

`US 9,943,526 B2
`
`3
`"Patient" refers to animals such as mammals, including,
`but not limited to, primates (e.g., humans), cows, sheep,
`goats, horses, dogs, cats, rabbits, rats, mice and the like. The
`patient can have a condition known to be treated by gluco(cid:173)
`corticoid antagonists such as mifepristone. Such conditions
`include, but are not limited to, psychiatric illnesses and
`hormonal disorders. In certain embodiments, the patient is a
`human. The patient can be male or female.
`"Cushing's syndrome" refers to an endocrine disease with
`an estimated incidence of approximately 10-15 per 1 million
`persons (Meier and Biller (1997) Endocrinol Metab Clin
`North Am 26:741-762), and is associated with an increased
`blood concentration of cortisol (hypercortisolism) over a
`long period of time. Cushing's syndrome is classified as
`either ACTH dependent or non ACTH dependent. ACTH
`dependent Cushing's syndrome is characterized by a chronic
`ACTH hypersecretion which stimulates the growth of the
`adrenal glands and the hypersecretion of corticosteroids.
`The most common underlying cause of ACTH dependent
`Cushing's syndrome is excessive production of ACTH by
`pituitary adenomas known as Cushing's disease. Cushing's
`syndrome resulting from the production of ACTH in another
`location than the pituitary gland is known as ectopic Cush(cid:173)
`ing's syndrome. Examples of ectopic sites include thymoma,
`medullary carcinoma of the thyroid, pheochromocytoma,
`islet cell tumors of the pancreas and small cell carcinoma of
`the lung. ACTH independent Cushing's syndromes are
`caused by adrenal tumors that can be either adenomas or
`carcinomas. Both adrenal adenomas and carcinomas are
`characterized by chronic cortisol hypersecretion.
`"Optimizing" refers to the process of testing mifepristone
`blood levels and adjusting the dosage of mifepristone
`administered to the patient in need in order to achieve
`mifepristone blood levels above 1631 ng/mL.
`"Treat", "treating" and "treatment" collectively refer to
`any indicia of success in the treatment or amelioration of an
`injury, pathology or condition, including any objective or
`subjective parameter such as abatement; remission; dimin(cid:173)
`ishing of symptoms or making the injury, pathology or 40
`condition more tolerable to the patient; slowing in the rate of
`degeneration or decline; making the final point of degen(cid:173)
`eration less debilitating; improving a patient's physical or
`mental well-being; or, in some situations, preventing the
`onset of dementia. The treatment or amelioration of symp(cid:173)
`toms can be based on objective or subjective parameters;
`including the results of a physical examination, neuropsy(cid:173)
`chiatric exams, and/or a psychiatric evaluation.
`"Testing" refers to determining the mifepristone blood
`levels in a patient. The testing can be performed by any
`suitable instrument, such as a plasma sampling collection
`device capable of detecting mifepristone serum levels.
`A patient "not already suffering from a condition indi(cid:173)
`cated for treatment with mifepristone" is a patient who is not
`suffering from a condition which is known in the art to be
`effectively treatable with mifepristone. Conditions known in
`the art to be effectively treatable with mifepristone include
`drug withdrawal, psychosis, dementia, stress disorders, and
`psychotic major depression.
`III. Method Of Optimizing Mifepristone Levels
`The present invention provides a method of optimizing
`mifepristone levels in patients with Cushing's syndrome
`such that the blood serum levels remain at efficacious levels.
`The method involves administering mifepristone for a week,
`testing the blood serum levels of the Cushing's patient, and
`adjusting the mifepristone dose to maintain the mifepristone
`blood serum levels of at least 1631 ng/mL.
`
`4
`The present invention provides a method for improving
`efficacy of mifepristone treatment in a patient suffering from
`Cushing's syndrome. The method includes treating the
`patient with seven or more daily doses of mifepristone over
`a period of seven or more days; testing the serum levels of
`the patient to determine whether the blood levels of mife(cid:173)
`pristone are greater than 1631 ng/mL; and adjusting the
`daily dose of the patient to achieve mifepristone blood levels
`greater than 1631 ng/mL. The patient treated in this method
`10 is not already suffering from a condition indicated for
`treatment with mifepristone, thereby improving the efficacy
`of mifepristone treatment for the patient suffering from
`Cushing's syndrome.
`The seven or more daily doses of mifepristone can each
`15 be administered by any means suitable, as described in more
`detail below. In some embodiments, each of the seven or
`more daily doses of mifepristone are administered orally.
`The seven or more daily doses of mifepristone can each
`be administered in any suitable dose. For example, the
`20 mifepristone can be administered in an amount of at least
`about 100 mg. The mifepristone can also be administered in
`an amount of about 300, 600, 900 or about 1200 mg. In some
`embodiments, the daily dose can be at least 300 mg. In some
`embodiments, the daily dose can be at least 600 mg. In some
`25 embodiments, the daily dose can be at least 900 mg. In some
`embodiments, the daily dose can be at least 1200 mg. Other
`daily doses are useful in the method of the present invention.
`The daily doses can be administered for any suitable
`period of time that is at least 7 days in length. For example,
`30 the daily doses can be for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
`17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days. The
`mifepristone can be administered for longer periods as
`required by the patient being treated. In some embodiments,
`the patient can be treated with 28 or more daily doses over
`35 a period of 28 or more days.
`The mifepristone blood levels can be tested by any means
`known to one of skill in the art. For example, the the testing
`can be performed by a plasma sampling collection device
`suitable for detecting mifepristone serum levels.
`The mifepristone blood levels can be at any suitable level
`to treat Cushing's syndrome. For example, the mifepristone
`blood levels can be greater than about 1400 ng/mL, 1450,
`1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900,
`2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800 or great
`45 than about 2900 ng/mL. In some embodiments, the mife(cid:173)
`pristone blood level can be greater than 1450 ng/mL. In
`some embodiments, the mifepristone blood level can be
`greater than 1469 ng/mL. In some embodiments, the mife(cid:173)
`pristone blood level can be greater than 1600 ng/mL. In
`so some embodiments, the mifepristone blood level can be
`greater than 1631 ng/mL. In some embodiments, the mife(cid:173)
`pristone blood level can be greater than 1662 ng/mL. In
`some embodiments, the mifepristone blood level can be
`greater than 1666 ng/mL. In some embodiments, the mife-
`55 pristone blood level can be greater than 1700 ng/mL. In
`some embodiments, the mifepristone blood level can be
`greater than 1800 ng/mL. In some embodiments, the mife(cid:173)
`pristone blood level can be greater than 1820 ng/mL. In
`some embodiments, the mifepristone blood level can be
`60 greater than 2000 ng/mL. In some embodiments, the mife(cid:173)
`pristone blood level can be greater than 2022 ng/mL.
`The daily dose can be adjusted to any suitable dose to
`maintain the mifepristone blood level above the necessary
`level. For example, if the mifepristone blood level is below
`65 1631 ng/mL, the daily dose can be increased to 600 mg from
`300 mg, to 900 mg from 600 mg, to 900 mg from 300 mg,
`to 1200 mg from 900 mg, to 1200 mg from 600 mg, or to
`
`4
`
`

`

`US 9,943,526 B2
`
`10
`
`5
`1200 mg from 300 mg. If after another seven daily doses, the
`mifepristone blood level is still not above the necessary
`level, the mifepristone daily can again be increased. For
`example, the mifepristone daily dose can be increased to 900
`mg from 600 mg, to 1200 mg from 900 mg, or to 1200 mg
`from 600 mg. In some embodiments, the adjusting step
`comprises increasing the daily dose of the patient to achieve
`mifepristone blood levels greater than 1631 ng/mL. Addi(cid:173)
`tional adjustments in the daily doses can be made to main-
`tain the mifepristone blood level above 1631 ng/mL.
`Any suitable percentage of the patient population can
`have the optimal response to administration of the mifepris(cid:173)
`tone. For example, at least 10, 20, 30, 40, 50, 60, 70, 80, 90
`or 100% of the patient population can achieve the optimal 15
`response to the mifepristone treatment. In some embodi(cid:173)
`ments, at least about 20% of the patient population can have
`the optimal response to administration of the mifepristone.
`In some embodiments, at least about 40% of the patient
`population can have the optimal response to administration 20
`of the mifepristone. In some embodiments, at least about
`60% of the patient population can have the optimal response
`to administration of the mifepristone.
`A. Patients in Need
`Patients amenable to treatment with mifepristone accord(cid:173)
`ing to the method of the present invention suffer from
`Cushing's syndrome. Cushing's syndrome is a disorder
`resulting from increased adrenocortical secretion of corti(cid:173)
`costeroid. Hyperfunction of the adrenal cortex may be
`adrenocorticotropic hormone (ACTH)-dependent or it may
`be independent of ACTH regulation, e.g. production of
`corticosteroid by an adrenocortical adenoma or carcinoma.
`A common cause of Cushing's syndrome is excessive pro(cid:173)
`duction of ACTH by the pituitary gland. This elevated level
`of ACTH in the bloodstream typically is produced by a
`pituitary adenoma (Cushing's disease), but in rare instances
`has a different etiology. Cushing's syndrome resulting from
`the production of ACTH in a location other than the pituitary
`gland is known as ectopic Cushing's syndrome. Examples of
`ectopic sites include thymoma, medullary carcinoma of the
`thyroid, pheochromocytoma, islet cell tumors of the pan(cid:173)
`creas and oat cell carcinoma of the lung. The overwhelming
`majority of Cushing's syndrome cases in humans, however,
`trace their etiology to a pituitary adenoma. Symptoms of
`Cushing's syndrome include weight gain, central obesity,
`steroid hypersecretion, elevated urinary cortisol excretion,
`moon face, weakness, fatigue, backache, headache, impo(cid:173)
`tence, mental status changes, muscle atrophy, and increased
`thirst and urination compared to mammals not suffering
`from this disease. Diagnosis and treatment of Cushing's
`syndrome remains a challenge (see Oldfield, E. W. eta!., N.
`Engl. J. Med., 325:897-905 (1991); Findling, J. W. et a!.,
`"Diagnosis and differential diagnosis of Cushing's syn(cid:173)
`drome," Endocrinol. Metab. Clin. North Am., 30:729-47
`(2001); Orth, D. N., "Cushing's syndrome," N Eng! J. Med.,
`332:791-803 (1995)). In experienced specialized centers,
`surgical resection of ACTH-secreting pituitary microad(cid:173)
`enomas offers an overall cure rate of about 70-80%, but for
`macroadenomas cure rates only approximate 30%, and the
`extensive surgical resection required portends significant
`risk to surrounding normal pituitary tissue, leading to partial
`or total hypopituitarism in about 80% of cases (Simmons, N.
`E. et a!., "Serum Cortisol response to transphenoidal surgery
`for Cushing disease," J. Neurosurg., 95:1-8 (2001); Mam(cid:173)
`palam, T. J. eta!., "Transsphenoidal microsurgery for Cush- 65
`ing's disease: A report of 216 cases," Ann. Intern. Med.,
`109:487-93 (1988); and Trainer, P. J. eta!., "Transsphenoidal
`
`6
`resection in Cushing's disease: undetectable serum cortisol
`as the definition of successful treatment," Clin. Endocrinol.,
`38:73-8 (1993)).
`B. Formulations of Mifepristone
`Formulations of the present invention include mifepris(cid:173)
`tone in combination with pharmaceutical excipients. Mife(cid:173)
`pristone is commercially available from a variety of sources
`such as Eurolabs Ltd. (London, England). Mifepristone can
`also be synthesized by one of skill in the art using known
`synthetic procedures.
`Mifepristone refers to a family of compositions also
`referred to as RU486, or RU38.486, or 17-beta-hydroxy-11-
`beta-( 4-dimethyl-aminophenyl)-17 -alpha-(1-propynyl)-es(cid:173)
`tra-4,9-dien-3-one ), or 11-beta-( 4dimethylaminophenyl)-
`17-beta-hydroxy-17 -alpha-(1-propynyl)-estra-4,9-dien-3-
`one ), or analogs thereof, which bind to the GR, typically
`with high affinity, and inhibit the biological effects initiated/
`mediated by the binding of any cortisol or cortisol analogue
`to a GR receptor. Chemical names for RU-486 vary; for
`example, RU486 has also been termed: llB[p-(Dimethyl(cid:173)
`amino )phenyl]-17B-hydroxy-17 -(1-propynyl)-estra-4,9-
`liB-( 4-dimethyl-aminophenyl)-17B-hydroxy-
`dien-3-one;
`17 A-(prop-1-ynyl)-estra-4,9-dien-3-one;
`17B-hydroxy-
`11 B-( 4-dimethy laminopheny 1-1 )-17 A -(propyny 1-1 )-estra -4,
`25 9-diene-3-one; 17B-hydroxy-11B-( 4-dimethylaminophenyl-
`1)-17 A-(propynyl-1)-E; (11B,17B)-11-[ 4-dimethylamino)(cid:173)
`phenyl]-17 -hydroxy-17 -(1-propynyl)estra-4,9-dien-3-one;
`liB-[ 4-(N,N-dimethylamino) phenyl]-17 A-(prop-1-
`and
`ynyl)-D-4,9-estradiene-17B-ol-3-one. Salts, hydrates and
`30 prodrug forms of mifepristone are also useful in the formu(cid:173)
`lations of the present invention.
`Formulations suitable for oral administration can consist
`of (a) liquid solutions, such as an effective amount of
`mifepristone suspended in diluents, such as water, saline or
`35 PEG 400; (b) capsules, sachets or tablets, each containing a
`predetermined amount of the active ingredient, as liquids,
`solids, granules or gelatin; (c) suspensions in an appropriate
`liquid; and (d) suitable emulsions. Tablet forms can include
`one or more of lactose, sucrose, mannitol, sorbitol, calcium
`40 phosphates, com starch, potato starch, microcrystalline cel(cid:173)
`lulose, gelatin, colloidal silicon dioxide, talc, magnesium
`stearate, stearic acid, and other excipients, colorants, fillers,
`binders, diluents, buffering agents, moistening agents, pre(cid:173)
`servatives, flavoring agents, dyes, disintegrating agents, and
`45 pharmaceutically compatible carriers. Lozenge forms can
`comprise the active ingredient in a flavor, e.g., sucrose, as
`well as pastilles comprising the active ingredient in an inert
`base, such as gelatin and glycerin or sucrose and acacia
`emulsions, gels, and the like containing, in addition to the
`so active ingredient, carriers known in the art.
`The pharmaceutical preparation is preferably in unit dos(cid:173)
`age form. In such form the preparation is subdivided into
`unit doses containing appropriate quantities of the active
`component. The unit dosage form can be a packaged prepa-
`55 ration, the package containing discrete quantities of prepa(cid:173)
`ration, such as packeted tablets, capsules, and powders in
`vials or ampoules. Also, the unit dosage form can be a
`capsule, tablet, cachet, or lozenge itself, or it can be the
`appropriate number of any of these in packaged form. The
`60 composition can, if desired, also contain other compatible
`therapeutic agents. Preferred pharmaceutical preparations
`can deliver the compounds of the invention in a sustained
`release formulation.
`C. Administration of Mifepristone
`The formulations of the present invention provide serum
`levels of mifepristone of at least 1631 ng/mL. The mifepris(cid:173)
`tone utilized in the pharmaceutical method of the invention
`
`5
`
`

`

`US 9,943,526 B2
`
`7
`is administered at the initial dosage of about 0.001 mg/kg to
`about 1000 mg/kg daily. A daily dose range of about 0.01
`mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200
`mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10
`mg/kg to about 50 mg/kg, can be used. The dosages,
`however, may be varied depending upon the requirements of
`the patient and the condition being treated. The dose admin(cid:173)
`istered to a patient, in the context of the present invention,
`should be sufficient to effect a beneficial therapeutic
`response in the patient over time. The size of the dose also 10
`will be determined by the existence, nature, and extent of
`any adverse side-effects that accompany the administration
`of a particular compound in a particular patient. Determi(cid:173)
`nation of the proper dosage for a particular situation is 15
`within the skill of the practitioner.
`Generally, treatment is initiated with six daily doses, with
`the blood levels tested on the day of the seventh daily dose
`in order to determine whether the dose used is providing a
`mifepristone blood level of at least 1631 ng/mL. The testing 20
`is also performed to ensure the blood levels are below those
`afforded by an LD50 dose of about 1000 mg/kg. If the
`mifepristone blood level is lower than 1631 ng/mL. Addi(cid:173)
`tional testing of mifepristone blood levels can be necessary
`in order to confirm a mifepristone blood level of at least 25
`1631 ng/mL or to adjust the mifepristone daily dose higher.
`For convenience, the total daily dosage may be divided and
`administered in portions during the day, if desired. In
`addition, the interval from initiation of treatment and testing
`for mifepristone blood levels can be as short as 1 daily dose, 30
`or up to 28 daily doses and longer.
`Mifepristone can be administered for any period of time,
`such as 7 daily doses over a period of seven days. Mife(cid:173)
`pristone can also be administered using more daily doses 35
`over a longer period of time, such as via 28 daily doses over
`a period of 28 days. Longer times for administration of
`mifepristone are also within the scope of the present inven-
`tion.
`D. Assay for Testing Mifepristone Levels
`Mifepristone levels can be determined by any method
`known in the art. Methods for detecting mifepristone levels
`include, but are not limited to, radio-immunoassay and mass
`spectrometry (MALDI, SELDI, LS/MS, LS/MS/MS, among
`others). Liquid chromatography mass spectrometry (LC/MS
`or LC-MS) separates compounds chromatographically
`before they are introduced to the ion source and mass
`spectrometer. It differs from GC/MS in that the mobile phase
`is liquid, usually a combination of water and organic sol(cid:173)
`vents, instead of gas. Most commonly, an electrospray 50
`ionization source is used in LC/MS.
`Tandem mass spectrometry (MS/MS) involves multiple
`steps of mass selection or analysis, usually separated by
`some form of fragmentation. A tandem mass spectrometer is
`one capable of multiple rounds of mass spectrometry. For 55
`example, one mass analyzer can isolate one peptide from
`many entering a mass spectrometer. A second mass analyzer
`then stabilizes the peptide ions while they collide with a gas,
`causing them to fragment by collision-induced dissociation
`(CID). A third mass analyzer then catalogs the fragments 60
`produced from the peptides. Tandem MS can also be done in
`a single mass analyzer over time as in a quadrupole ion trap.
`There are various methods for fragmenting molecules for
`tandem MS, including collision-induced dissociation (CID),
`electron capture dissociation (ECD), electron transfer dis- 65
`soc1atwn
`(ETD),
`infrared multiphoton dissociation
`(IRMPD) and blackbody infrared radiative dissociation
`
`8
`(BIRD). One of skill in the art will appreciate that other
`assays for testing mifepristone levels are known to one of
`skill in the art.
`In some embodiments, the assay can be performed as
`follows. Blood is collected from a patient in a vacutainer
`containing sodium heparin. The blood is centrifuged and the
`resulting plasma frozen at an appropriate temperature until
`assay. In some embodiments, the temperature is about -70°
`C. In other embodiments, other blood components can be
`collected and stored. Prior to analysis, the plasma is thawed
`and a fraction of the plasma is mixed with an internal
`standard in a solvent such as acetonitrile, to obtain a fixed
`concentration of the standard. In some embodiments, the
`internal standard can be mifepristone-d4. The concentration
`of the internal standard is selected in order to be greater than
`the expected concentration of mifepristone in the plasma.
`For example, the internal standard can have a concentration
`of 2000 ng/mL. One of skill in the art will appreciate that
`other internal standards, and other concentrations, are useful
`in the present invention.
`Base is then added to the sample solution. The base can
`be any amine or monium base, such as monium
`hydroxide. One of skill in the art will appreciate that other
`bases are useful in the present invention.
`Solvent is then added to the solution and the mifepristone
`(along with the internal standard) are extracted from the
`plasma. Solvents useful for the extraction of mifepristone
`include, but are not limited to, hexanes, pentanes, ethers
`(such as diethylether, tetrahydrofuran and methyl-t-butyl
`ether (MTBE)), ethyl acetate, chloroform and methylene
`chloride. One of skill in the art will appreciate that other
`solvents are useful in the present invention.
`Following separation and concentration of the organic