111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US010195214B2
`
`c12) United States Patent
`Belanoff
`
`(10) Patent No.: US 10,195,214 B2
`(45) Date of Patent:
`*Feb. 5, 2019
`
`(54) CONCOMITANT ADMINISTRATION OF
`GLUCOCORTICOID RECEPTOR
`MODULATORS AND CYP3A INHIBITORS
`
`(71) Applicant: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`
`(72)
`
`Inventor: Joseph K. Belanoff, 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.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 15/627,359
`
`(22) Filed:
`
`Jun. 19, 2017
`
`(65)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`Prior Publication Data
`
`Nov. 16, 2017
`US 2017/0326157 Al
`Related U.S. Application Data
`
`Provisional application No. 62/465,772, filed on Mar.
`1, 2017, provisional application No. 62/466,867, filed
`on Mar. 3, 2017.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311575
`A61K 311567
`A61K 311496
`A61K 45106
`U.S. Cl.
`CPC .......... A61K 311575 (2013.01); A61K 311496
`(2013.01); A61K 45106 (2013.01)
`Field of Classification Search
`CPC .... A61K 31/575; A61K 31/567; A61K 45/06;
`A61P 3/10
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`12/2015 Newell-Price
`9,216,221 B2
`2010/0135956 A1
`6/2010 Gant eta!.
`2010/0261693 A1 * 10/2010 Ulmann
`
`2016/0067264 A1
`2017/0281651 A1
`
`3/2016 Newell-Price
`10/2017 Belanoff
`
`A61K 31/567
`514/179
`
`FOREIGN PATENT DOCUMENTS
`
`wo
`wo
`wo
`wo
`
`2008060391 A2
`2009050136 A2
`2010052445 A1
`2016187347 A1
`
`5/2008
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`Castinetti eta!., "Ketoconazole in Cushing's Disease: Is It Worth a
`Try?", J Clin Endocrinol Metab, May 2014, 99(5):1623-1630.
`Fleseriu et a!., "Mifepristone, a Glucocorticoid Receptor Antago(cid:173)
`nist, Produces Clinical and Metabolic Benefits in Patients with
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`Gal et al., "Effect ofketoconazole on steroidogenic human granulosa(cid:173)
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`Latrille et al., "AComparativee Study of the Effects ofKetoconazole
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`Albertson eta!., "Effect of the antiglucocorticoid RU486 on adrenal
`steroidogenic enzyme activity and steroidogenesis," EP J. ofEndrocrino.
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`Asser et al., "Autocrine positive regulatory feedback of glucocorticoid
`secretion: Glucocorticoid receptor directly impacts H295R human
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`Bertagna eta!., "Pituitary-Adrenal Response to the Antiglucocorticoid
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`
`(Continued)
`
`Primary Examiner- Jeffrey S Lundgren
`Assistant Examiner- Chris E Simmons
`(74) Attorney, Agent, or Firm- Kilpatrick Townsend &
`Stockton LLP
`
`ABSTRACT
`(57)
`Applicant provides methods of treating diseases including
`Cushing's syndrome and hormone-sensitive cancers by con(cid:173)
`comitant administration of a glucocorticoid receptor antago(cid:173)
`nist (GRA) and steroidogenesis inhibitors, and by concomi(cid:173)
`tant administration of a GRA and CYP3A inhibitors.
`Applicant provides methods of treating diseases including
`Cushing's syndrome and hormone-sensitive cancers by con(cid:173)
`comitant administration of mifepristone and ketoconazole.
`Subjects treated with CYP3A inhibitors or steroidogenesis
`inhibitors may suffer from toxicity or other serious adverse
`reactions; concomitant administration of other drugs would
`be expected to increase the risk of such toxicity and adverse
`reactions. Applicant has surprisingly found that GRAs may
`be administered to subjects receiving CYP3A inhibitors or
`steroidogenesis inhibitors such as ketoconazole without
`increasing risk adverse reactions; for example, Applicant has
`found that mifepristone may be concomitantly administered
`with ketoconazole (a CYP3A inhibitor and a steroidogenesis
`inhibitor), providing safe concomitant administration of the
`GRA and ketoconazole. In embodiments, the GRA dose may
`be reduced.
`
`Korlym™ (mifepristone) [package insert]. Corcept Therapeutics,
`Inc., Menlo Park, CA; Feb. 2012. 26 pages.*
`
`13 Claims, 1 Drawing Sheet
`
`1
`
`TEVA1001
`
`

`

`US 10,195,214 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Chu eta!., "Successful Long-Term Treatment of Refractory Cushing's
`Disease with High-Dose Mifepristone (RU 486)," J. Clin Endocri(cid:173)
`nology Metab, Aug. 2001, 86(8):3568-3573.
`Cuneo et a!., Metyrapone pre-treated inferior petrosal sinus sam(cid:173)
`pling in the differential diagnosis of ACTH-dependent Cushing's
`syndrome. Clin Endocrinol (Oxf). May 1997;46(5):607-18.
`Ehrenkranz et a!. "SUN-66: Using Mifepristone to Differentiate
`Cushing's Disease from Cushing's Syndrome," The Endocrine
`Society's 95 1
`h Annual Meeting and Expo, Jun. 15-18, 2013 (San
`Francisco) Abstract.
`El-Shafie, et al., "Adrenocorticotropic Hormone-Dependent Cushing's
`Syndrome: Use of an octreotide trial to distinguish between pitu(cid:173)
`itary or ectopic sources," Sultan Qaboos University Medical Jour(cid:173)
`nal, vol. 15, Issue 1, pp. 120-123 (Epub. Jan. 21, 2015).
`Fein, eta!., Sustained weight loss in patients treated with mifepristone
`for Cushing's syndrome: a follow-up analysis of the SEISMIC
`study and long-term extension. BMC Endocr Disord. 15:63 (20 15).
`Gross et al., "Mifepristone Reduces Weight Gain and Improves
`Metabolic Abnormalities Associated With Risperidone Treatment in
`Normal Men." Obesity vol. 18 No. 12/Dec. 2010; Published online
`Mar. 25, 2010.
`Healy et a!., "Pituitary and adrenal responses to the anti(cid:173)
`progesterone and anti-glucocorticoid steroid RU486 in primates," J.
`Clin Endocrinol Metab (1983) 57(4):863-865.
`Lee et a!., Office of Clinical Pharmacology Review NDA 20687
`(Addendum, Korlym™, Mifepristone) (2012).
`Lely VanDer A-Jet a!., "Rapid Reversal of Acute Psychosis in the
`Cushing Syndrome with the Cortisol-Receptor Antagonist Mifepristone
`(RU 486)," Annals oflnternal Medicine, Jan. 15, 1991, 114(2):143-
`144.
`Medical Encyclopedia ofMedline (http:/ /www.nlm.nih. gov /medlineplus/
`ency/article/003430.htm) 4 pages, Oct. 2005.
`Moncet et a!. Ketoconazole therapy: an efficacious alternative to
`achieve eucortisolism in patients with Cushing's syndrome. Medicina
`67:26-31 (2007).
`Reimondo eta!., "The corticotrophin-releasing hormone test is the
`most reliable noninvasive method to differentiate pituitary from
`ectopic ACTH secretion in Cushing's syndrome," Clinical Endo(cid:173)
`crinology, (2003) 58:718-724.
`
`Ritzel eta!.. "ACTH after 15 min distinguishes between Cushing's
`disease and ectopic Cushing's syndrome: a proposal for a short and
`simple CRH test," Europe an Journal of Endocrinology, vol. 173,
`No.2, pp. 197-204 (2015).
`Sarkar, "Mifepristone: bioavailability, pharmacokinetics and use(cid:173)
`effectiveness," European Journal of Obstetrics and Gynecology and
`Reproductive Biology, vol. 101, pp. 113-120 (2002).
`Tsigos, "Differential Diagnosis and Management of Cushing's
`Syndrome", Ann. Rev. Med. vol. 47, pp. 443-461 (1996).
`PCT/US2017/013974, International Search Report and Written Opin(cid:173)
`ion, dated Jan. 18, 2017, pp. 1-12.
`PCT/EP2008/063699, International Search Report, dated May 6,
`2009, pp. 2-6.
`FDA Label for Korlym® dated Oct. 2016.
`U.S. Appl. No. 15/627,368, "Non-Final Office Action", dated Aug.
`8, 2017, 13 pages.
`Greenblatt eta!. "Ritonavir is the best alternative to ketoconazole as
`an index inhibitor of cytochrome P450-3A in drug-drug interaction
`studies," Brit. J. Clin. Pharmacol. 80(3)342-350 (20 15)).
`"Clinical Drug Interaction Studies-Study Design, Data Analysis,
`and Clinical Implications Guidance for Industry" dated Oct. 2017
`http s: I /www. fda. gov /Drug s/Devel opmen tApprov alPro cess/
`DevelopmentResources/DruginteractionsLabeling/ucm093606.htm
`(accessed Dec. 11, 20 17).
`"Drug Development and Drug Interactions: Table of Substrates,
`Inhibitors and Inducers" https:/ /www.fda.gov/Drugs/DevelopmentAp(cid:173)
`provalProcess/DevelopmentResources/DruginteractionsLabeling/
`ucm093664.htm (FDA website (cached), accessed Dec. 8, 2017).
`Chapter 1, "Pharmacokinetics: The Dynamics of Drug Absorption,
`Distribution, and Elimination", Benet LZ et a!., in The Pharmaco(cid:173)
`logical Basis of Therapeutics, Eighth Edition, Pergamon Press,
`Elmsford, New York, USA, 1990, pp. 3-32.
`U.S. Appl. No. 15/627,368, final Office action dated Dec. 5, 2017
`for U.S. Application entitled "Concomitant Administration of
`Glucocorticoid Receptor Modulators and CYP3Aor Steroidogenesis
`Inhibitors", filed Jun. 19, 2017; inventor J. Belanoff, Applicant:
`Corcept Therapeutics; published as US 2017-0281651 AI.
`Morgan et a!., "Mifepristone for Management of Cushing's Syn(cid:173)
`drome", Pharmacotherapy, Feb. 21, 2013, 33(3):319-329.
`Varis eta!., "The Effect ofltraconazole on the Pharmacokinetics and
`Pharmacodynamics of Oral Prednisolone", European Journal of
`Clinical Pharmacology, Apr. 2000, 56(1):57-60.
`PCT/US2018/020336 , "International Search Report and Written
`Opinion", dated May 15, 2018, 11 pages.
`* cited by examiner
`
`2
`
`

`

`U.S. Patent
`
`Feb.5,2019
`
`US 10,195,214 B2
`
`•14
`
`21
`
`Stw:ly Day
`
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`

`

`US 10,195,214 B2
`
`1
`CONCOMITANT ADMINISTRATION OF
`GLUCOCORTICOID RECEPTOR
`MODULATORS AND CYP3A INHIBITORS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of, and priority to, U.S.
`Provisional Application Ser. No. 62/465,772, filed Mar. 1,
`2017, and U.S. Provisional Application Ser. No. 62/466,867,
`filed Mar. 3, 2017, the entire contents of both of which
`applications are hereby incorporated by reference in their
`entireties.
`
`BACKGROUND
`
`Steroid molecules, such as steroid hormones, play an
`important role in bodily functions and in bodily responses to
`infectious and other diseases, and to the environment. Many
`steroid molecules are synthesized in the body, or are pro(cid:173)
`duced from molecules consumed in the diet. Steroid mol(cid:173)
`ecules which act as hormones in the body include estrogen,
`progesterone, testosterone, and cortisol. Some steroid mol(cid:173)
`ecules have medicinal effects. Inhibition of steroid synthesis
`or metabolism can be useful in the treatment of some
`disorders.
`Cortisol, a steroid molecule, plays an important role in
`many bodily functions. Cortisol exerts effects by binding to
`cortisol receptors, which are present in most tissues in the
`body. However, dysregulation of cortisol may have adverse
`effects on a subject. For example, Cushing's syndrome,
`caused by excess levels of cortisol, is characterized by
`symptoms including elevated blood pressure, elevated blood
`glucose, increased weight, increased mid-section perimeter,
`other pre-diabetic symptom, a "moon-face" facial appear- 35
`ance, immune suppression, thin skin, acne, depression,
`hirsutism, and other symptoms. Clinical manifestations of
`Cushing's syndrome include abnormalities in glucose con(cid:173)
`trol, requirement for anti-diabetic medication, abnormalities
`in insulin level, abnormal psychiatric symptoms, cushingoid 40
`appearance, acne, hirsutism, and increased or excessive
`body weight, and other symptoms.
`One effective treatment of cortisol dysregulation is to
`block the binding of cortisol to cortisol receptors, or to block
`the effect of cortisol binding to cortisol receptors. Mifepris- 45
`tone binds to cortisol receptors, and acts to block such
`binding and to block the effect of cortisol on tissues.
`11 ~-( 4-dimethylaminophenyl)-17~-hy­
`Mifepristone
`is
`droxy-17a-(1-propynyl)-estra-4,9-dien-3-one ).
`Another effective treatment of cortisol dysregulation is to 50
`reduce the synthesis of cortisol, e.g., by reducing or blocking
`steroid synthesis. A "steroidogenesis inhibitor" is a com(cid:173)
`pound which reduces or blocks the synthesis of steroid
`molecules (including, e.g., cortisol) when administered to a
`subject. Steroidogenesis inhibitors include, for example, 55
`ketoconazole, metyrapone, etomidate, and other drugs.
`Many enzymes are involved in steroid synthesis and in
`steroid metabolism, including cytochrome P450 enzymes,
`encoded by CYP genes. Inhibiting steroid synthesis may
`lower the levels of steroids, including, e.g., cortisol, in the 60
`blood. For example, CYP3A enzymes play important roles
`in the synthesis of steroid hormones such as cortisol.
`However, many drugs inhibit the levels or actions of
`CYP3A gene products (termed "inhibit CYP3A"). The fol(cid:173)
`lowing drugs inhibit CYP3A: ketoconazole, itraconazole, 65
`fluconazole, cimetidine, nefazodone, ritonavir, nelfinavir,
`indinavir, atazanavir, amprenavir, fosamprenavir, bocepre-
`
`2
`vir, clarithromycin, conivaptan, lopinavir, posaconazole,
`saquinavir,
`telaprevir,
`telithromycin, and voriconazole,
`among many drugs which inhibit CYP3A. For example, the
`following drugs strongly inhibit CYP3A (i.e., increase AUC
`(area under the concentration-time curve) by 10-fold or
`greater of sensitive index substrates), either alone or in
`combination with other drugs: boceprevir, cobicistat,
`conivaptan, danoprevir and ritonavir, elvitegravir and rito(cid:173)
`navir, indinavir, ritonavir, itraconazole, ketoconazole, lopi-
`10 navir, paritaprevir, ombitasvir, dasabuvir, posaconazole,
`saquinavir, telaprevir, tipranavir, troleandomycin, and vori(cid:173)
`conazole.
`Ketoconazole is an exemplary and an important steroido(cid:173)
`genesis inhibitor and is a strong CYP3A inhibitor. Ketocon-
`15 azole (chemical name: 1-acetyl-4-[ 4-[[2-(2,4-dichlorophe(cid:173)
`nyl)-2-[ (lH -imidazol-1-yl)-methyl]-1 ,3-dioxolan-4-yl]
`the
`methoxy]phenyl]piperazine)
`is
`administered
`for
`treatment of fungal infections; it also affects steroid metabo(cid:173)
`lism by inhibiting steroidogenesis, and has anti-glucocorti-
`20 coid and anti-androgen effects due to its interference with
`enzymatic conversion of cholesterol to hormones such as
`cortisol and testosterone. Ketoconazole has effects on liver
`enzymes and the gastrointestinal (GI) tract, among other
`effects
`(Fleseriu and Castinetti, Pituitary 19:643-653
`25 (2016)).
`Ketoconazole inhibits steroid synthesis and is thus useful
`in the treatment Cushing's syndrome; in the treatment of
`prostate cancer and other androgen-sensitive cancers; to
`reduce estrogen or progesterone production (e.g., in patients
`30 with hormone-sensitive cancers such as breast cancer and
`ovarian cancer); and in other treatments.
`A drug such as ketoconazole is typically metabolized and
`excreted by a subject over time following administration. An
`effective dose is determined based on the expected amounts
`of metabolism and excretion of the drug. Changes in the
`amounts or rates of metabolism and/or excretion of a drug
`will affect the dose required, and may make an otherwise
`safe dose, if metabolism or excretion changes, into either a
`less, or ineffective dose, or a more effective or even toxic
`dose.
`However, although sometimes clinically useful, ketocon(cid:173)
`azole may have adverse, including seriously toxic, effects
`(Fleseriu and Castinetti, Pituitary 19:643-653 (2016)). The
`U.S. Food and Drug Administration issued a Drug Safety
`Communication (Jul. 26, 2013 Safety Announcement
`regarding Nizoral® (ketoconazole)) warning of potentially
`fatal liver damage associated with oral ketoconazole treat(cid:173)
`ment and warning of the risk of adrenal insufficiency, also a
`potentially fatal disorder. The Safety Announcement
`warned: "Nizoral tablets can cause liver injury, which may
`potentially result in liver transplantation or death." The
`Safety Announcement further stated: "Nizoral tablets may
`interact with other drugs a patient is taking and can result in
`serious and potentially life-threatening outcomes, such as
`heart rhythm problems." Thus, ketoconazole can be quite
`toxic if administered in excessive amounts, or if it is
`administered to sensitive individuals, particularly when
`administered systemically (as opposed, e.g., to topically).
`This toxicity can lead to liver damage (sometimes requiring
`liver transplantation). Other CYP3A inhibitors, including,
`e.g., itraconazole, ritonavir, and other CYP3A inhibitors as
`discussed herein, may have similar effects and may require
`similar warnings.
`The simultaneous, or nearly simultaneous (e.g., concomi(cid:173)
`tant) presence of two drugs in a subject may alter the effects
`of one or the other, or both, drugs. Such alterations are
`termed drug-drug interactions. For example, the required
`
`4
`
`

`

`US 10,195,214 B2
`
`3
`dose of a drug is often strongly affected by taking the
`amount and rate of its degradation in, and elimination from,
`the body (e.g., by liver or kidney action). However, the
`presence of a second drug in the body, which is also being
`acted upon by the liver and kidney, can have significant
`effects on the amount and rate of degradation of the first
`drug, and can increase the amount of the first drug that
`remains in the body at a given time beyond the amount that
`would have been present at that time in the absence of the
`second drug. Thus, the presence of a second drug can often 10
`increase the effective dose of the first drug. Where the first
`drug has toxic side effects, such an increase in effective dose
`of the first drug may lead to dangerous toxicity that would
`not have been expected were the second drug not present. 15
`Concomitant administration of different drugs often leads
`to adverse effects since the metabolism and/or excretion of
`each drug may reduce or interfere with the metabolism
`and/or excretion of the other drug(s), thus increasing the
`effective concentrations of those drugs as compared to the 20
`effective concentrations of those drugs when administered
`alone. Thus, concomitant administration of drugs is often
`expected to increase the risk of toxic effects of one or both
`of the co-administered drugs. Some drugs, such as ketocon(cid:173)
`azole, present risk of liver damage (including severe cases 25
`including liver failure and even requiring liver transplants)
`and other toxic effects when administered alone; the risk of
`such toxic effects is believed to be increased when other
`drugs are concomitantly administered. Where a drug, such
`as ketoconazole, is known to present a high risk of toxic
`effects, clinicians will typically avoid its concomitant
`administration with other drugs.
`However, patients often require treatment with multiple
`drugs, so that the potential toxicity of drugs such as keto(cid:173)
`conazole present disadvantages that can have deleterious
`consequences for the patient who requires ketoconazole
`treatment, or may require foregoing the use ofketoconazole
`or of some other drug which may have otherwise been
`required for successful treatment.
`Accordingly, improved methods of treatment allowing the
`administration of other drugs along with CYP3A inhibitors
`(such as, e.g., ketoconazole) and along with steroidogenesis
`inhibitors (such as, e.g., ketoconazole) are desired.
`
`SUMMARY
`
`Applicant discloses herein that CYP3A inhibitors such as,
`e.g., ketoconazole, may be concomitantly administered with
`glucocorticoid receptor modulators (GRMs) such as the GR
`antagonik (GRA) mifepristone. Such concomitant adminis(cid:173)
`tration of a CYP3A inhibitor such as ketoconazole and a
`GRM such as mifepristone is believed to be safe for the
`subject, and to provide the therapeutic benefits of both drugs
`to the subject, and may allow the reduction in the amount of
`a GRM, or of a CYP3A inhibitor, administered to the
`subject; such reduction may reduce the risk of toxic effects
`of the CYP3A inhibitor concomitantly administered with the
`GRM. In embodiments, the CYP3A inhibitor is a strong
`CYP3A inhibitor. Such concomitant administration of a
`CYP3A inhibitor such as ketoconazole and a GRM such as
`mifepristone is believed to be safe for the subject, and to
`provide the therapeutic benefits of both drugs to the subject,
`may allow the reduction in the amount of GRM adminis(cid:173)
`tered to the subject, and may allow the reduction in the
`amount of a CYP3A inhibitor administered to the subject;
`such reductions may improve treatment of the patient and
`may reduce the risk of toxic effects of the CYP3A inhibitor.
`
`4
`Applicant discloses herein that steroidogenesis inhibitors
`may be concomitantly administered with glucocorticoid
`receptor modulators (GRMs) such as the GR antagonist
`(GRA) mifepristone. Such concomitant administration of a
`steroidogenesis inhibitor and a GRM such as mifepristone is
`believed to be safe for the subject, and to provide the
`therapeutic benefits of both drugs to the subject, and may
`allow concomitant administration of a GRA and a steroido-
`genesis inhibitor, may allow the reduction of the amount of
`GRM administered to the subject, or may allow the reduc(cid:173)
`tion in the amount of a steroidogenesis inhibitor adminis-
`tered to the subject; such reductions may reduce the risk of
`toxic effects of the steroidogenesis inhibitor. Such concomi(cid:173)
`tant administration of a steroidogenesis inhibitor and a GRM
`such as mifepristone is believed to be safe for the subject,
`and to provide the therapeutic benefits of both drugs to the
`subject, and may allow the reduction in the amount of GRM
`or of a steroidogenesis inhibitor administered to the subject;
`such reduction may improve treatment of the subject and
`may reduce the risk of toxic effects of the steroidogenesis
`inhibitor.
`For example, Applicant has surprisingly discovered that
`mifepristone may be administered to patients concomitantly
`receiving ketoconazole. For example ketoconazole may be
`administered to patients previously, or concomitantly, also
`receiving mifepristone so that the patient concomitantly
`receives ketoconazole and mifepristone. Such concomitant
`administration ofketoconazole and mifepristone is typically
`safe for the patient, provides the therapeutic benefits of both
`30 drugs to the patient, and may allow the reduction in the
`amount of mifepristone administered to the subject; such
`reduction may provide an effective dose of mifepristone that
`is a lower dose, yet still provides similar plasma mifepris(cid:173)
`tone levels as, and may be as effective as, the dose of
`35 mifepristone administered in the absence of ketoconazole.
`Such concomitant administration ofketoconazole and mife(cid:173)
`pristone provides the therapeutic benefits of both drugs to
`the patient, may allow a reduction in the amount of mife(cid:173)
`pristone administered to the patient, and may allow the
`40 reduction in the amount ofketoconazole administered to the
`patient; such reduction may reduce the risk of toxic effects
`of ketoconazole, and may improve the treatment of the
`patient.
`Applicant's surprising discovery is believed to apply to
`45 patients suffering from a disease or disorder and receiving a
`CYP3A inhibitor, including a strong CYP3A inhibitor such
`as ketoconazole; such patients suffering from a disease or
`disorder may be safely administered a GRM, such as mife(cid:173)
`pristone, concomitantly with the administration of a CYP3A
`50 inhibitor such as ketoconazole. Such concomitant adminis(cid:173)
`tration is believed to be safe for the patient. For example,
`concomitant administration of ketoconazole and mifepris(cid:173)
`tone surprisingly does not increase the risk of ketoconazole
`toxicity in the patient, and is believed to be safe for the
`55 patient. In particular, Applicant discloses herein that Cush(cid:173)
`ing's syndrome patients receiving ketoconazole may be
`safely administered mifepristone concomitantly with the
`administration of ketoconazole. Such concomitant adminis(cid:173)
`tration of ketoconazole and mifepristone to a patient suffer-
`60 ing from Cushing's syndrome is believed to be safe for the
`patient suffering from Cushing's syndrome, which is char(cid:173)
`acterized by hypercortisolism. Patients suffering from Cush(cid:173)
`ing's syndrome, such as those suffering from endogenous
`Cushing's syndrome, may suffer hyperglycemia secondary
`65 to hypercortisolism. Concomitant administration of a GRA
`(such as, e.g., mifepristone) and a CYP3Ainhibitor (such as,
`e.g., ketoconazole) as disclosed herein is believed to be safe,
`
`5
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`

`US 10,195,214 B2
`
`5
`and to be suitable for controlling hyperglycemia secondary
`to hypercortisolism in a patient with endogenous Cushing's
`syndrome.
`In embodiments, a method of treating a patient with
`Cushing's syndrome, the patient currently taking a GRA at
`an original dosage, comprises reducing the amount of GRA
`from said original dosage to an adjusted dosage that is less
`than the original dosage when the patient is receiving
`concomitant administration of a CYP3A inhibitor. In
`embodiments, a method of controlling hyperglycemia sec(cid:173)
`ondary to hypercortisolism in a patient with endogenous
`Cushing's syndrome, the patient currently taking a GRA at
`an original dosage, comprises reducing the amount of GRA
`from said original dosage to an adjusted dosage that is less
`than the original dosage when the patient is receiving 15
`concomitant administration of a CYP3A inhibitor. In
`embodiments of such methods, the adjusted dosage is less
`than the original dosage by at least an amount selected from
`about 5%, 10%, 15%, 20%, 25%, 30%, 33 113%, 35%, 40%,
`45%, 50%, 55%, 60%, 65%, 66 213%, 70%, 75%, 80%, 85%, 20
`and 90% of the original dosage. In embodiments, the
`adjusted dosage is less than the original dosage by at least
`10% of the original dosage. In embodiments, the adjusted
`dosage is less than the original dosage by at least 25% of the
`original dosage. In embodiments, the adjusted dosage is less 25
`than the original dosage by at least 33 113% of the original
`dosage. In embodiments, the adjusted dosage is less than the
`original dosage by at least 50% of the original dosage.
`In embodiments, where a GRM such as mifepristone
`would be prescribed at a first GRM dose, the amount of the 30
`GRM (such as mifepristone) administered, when co-admin(cid:173)
`istered with a steroidogenesis inhibitor or CYP3A inhibitor
`such as ketoconazole, may be reduced to a reduced GRM
`dose that has a smaller amount of GRM as compared to the
`first GRM dose yet provide effective treatment at the 35
`reduced GRM dose co-administered with a steroidogenesis
`inhibitor such as ketoconazole. In embodiments, the clinical
`status of a subject receiving a reduced GRM dose concomi(cid:173)
`tantly with a steroidogenesis inhibitor may be monitored for
`clinical response, e.g., for clinical response to the GRM 40
`(such as mifepristone). Monitoring for clinical response may
`include monitoring for clinical effect of the GRM, including
`clinical efficacy of the GRM; for clinical effect of a ste(cid:173)
`roidogenesis inhibitor of CYP3A inhibitor; for possible
`adverse reaction to a steroidogenesis inhibitor or CYP3A 45
`inhibitor, or the use of a steroidogenesis inhibitor or CYP3A
`inhibitor in combination with the GRM; for possible side(cid:173)
`effects of a steroidogenesis inhibitor or CYP3A inhibitor; for
`possible side-effects of the use of a steroidogenesis inhibitor
`or CYP3A inhibitor in combination with the GRM; or 50
`combinations thereof.
`the reduced GRM dose may be
`In embodiments,
`increased as necessary and as safe for the patient according
`to such monitoring of the patient. In embodiments, the
`reduced GRM dose may be titrated upwards as necessary 55
`and as safe for the subject according to such monitoring of
`the patient in order to achieve effective treatment of Cush(cid:173)
`ing's syndrome while remaining safe for the patient with
`regard to possible adverse effects of the concomitant admin(cid:173)
`istration of the GRM and the CYP3A inhibitor, or of the 60
`concomitant administration of the GRM and the steroido-
`genesis inhibitor.
`In embodiments, where a GRM such as mifepristone
`would be prescribed at a first GRM dose, the amount of the
`GRM (such as mifepristone) administered, when co-admin(cid:173)
`istered with a CYP3A inhibitor, including a strong CYP3A
`inhibitor such as ketoconazole, may be reduced to a reduced
`
`6
`GRM dose that has a smaller amount of GRM as compared
`to the first GRM dose yet provide effective treatment at the
`reduced GRM dose co-administered with a CYP3A inhibitor
`such as ketoconazole. In embodiments, the clinical status of
`a patient receiving a reduced GRM dose concomitantly with
`a CYP3A inhibitor may be monitored, e.g., for clinical effect
`of the GRM, for clinical effect of the CYP3A inhibitor, for
`possible adverse reaction to the CYP3A inhibitor or its use
`in combination with the GRM, for possible side-effects of
`10 the CYP3A inhibitor or its use in combination with the
`GRM, or combinations thereof. In embodiments,
`the
`reduced GRM dose may be increased as necessary and as
`safe for the patient according to such monitoring of the
`patient. In embodiments, the reduced GRM dose may be
`titrated upwards as necessary and as safe for the patient
`according to such monitoring of the patient in order to
`achieve effective treatment of Cushing's syndrome while
`remaining safe for the patient with regard to possible
`adverse effects of the concomitant administration of the
`GRM and the CYP3A inhibitor.
`Accordingly, Applicant discloses herein that a steroido(cid:173)
`genesis inhibitor may be administered to patients concomi(cid:173)
`tantly receiving administration of a GRM. Accordingly,
`Applicant discloses herein that a CYP3A inhibitor may be
`administered to patients concomitantly receiving adminis(cid:173)
`tration of a GRM. For example, Applicant discloses herein
`that ketoconazole, a steroidogenesis inhibitor and a CYP3A
`inhibitor, may be administered to patients suffering from a
`disease or disorder, such as, e.g., Cushing's syndrome, who
`are concomitantly receiving administration of a GRM such
`as mifepristone. Such concomitant administration of both a
`GRA (such as mifepristone) and a CYP3Ainhibitor (such as
`ketoconazole) may be administered to a patient suffering
`from endogenous Cushing's syndrome to control hypergly(cid:173)
`cemia secondary to hypercortisolism in the patient.
`Accordingly, Applicant discloses herein that GRMs may
`be administered to subjects previously, or concomitantly,
`also receiving administration of a steroidogenesis inhibitor
`or a CYP3A inhibitor. For example, Applicant discloses
`herein that GRMs may be administered to subjects suffering
`from a disease or disorder, such as, e.g., Cushing's syn-
`drome, who previously, or are concomitantly, also receiving
`administration of a steroidogenesis inhibitor or a CYP3A
`inhibitor such as ketoconazole. Applicant discloses methods
`for concomitant administration of a GRM and a steroido(cid:173)
`genesis or CYP3A inhibitor such as ketoconazole useful for
`treating a subject in need of such administration. Subjects in
`need of such administration include subjects suffering from
`a disease or disorder, and include subjects suffering from
`Cushing's syndrome. Applicant further discloses that such
`administration of a GRM and a steroidogenesis or a CYP3A
`inhibitor such as ketoconazole is typically safe for the
`subject, and provides the therapeutic benefits of both drugs
`to the subject. In embodiments, such concomitant adminis(cid:173)
`tration of a steroidogenesis or a CYP3A inhibitor such as
`ketoconazole and a GRM may allow the reduction i