Use of glucocorticoid receptor antagonists in combination with glucocorticoids to treat adrenal insufficiency

Abstract

This invention provides for a method of treating secondary adrenal insufficiency by co-administrating therapeutically effective amounts of a glucocorticoid and a glucocorticoid receptor antagonist to the patient in need thereof. In some embodiments, the method includes the proviso that the patient not be otherwise in need of treatment with a glucocorticoid and a glucocorticoid receptor antagonist. The treatment method can increase the patient's morning or basal cortisol level to at least about 12 μg/dL or a standard control level, and in turn, expedite significantly the recovery of the HPA axis. The method provided herein can improve health outcomes and life-threatening complications associated with secondary adrenal insufficiency.

Claims

1. A method of treating secondary adrenal insufficiency, the method comprising co-administering a therapeutically effective amount of a glucocorticoid (GC) and a non-steroidal glucocorticoid receptor antagonist (GRA) to a patient in need thereof, wherein administering said non-steroidal GRA comprises administering initial low dose amounts of the non-steroidal GRA once per day along with initial high dose amounts of said GC administration for at least a week, wherein said once-daily initial low dose amount said non-steroidal GRA is between 100 milligrams (mg) and 150 mg of the non-steroidal GRA, and wherein said initial high dose amount of said GC is between 15 and 30 mg of the GC, and then continuing to administer the GC and continuing to administer the non-steroidal GRA once per day, wherein said continued once per day non-steroidal GRA administration is at a non-steroidal GRA dose amount that is greater than said initial GRA low dose amount, and wherein said continued GC administration is at a GC dose amount that is less than said initial GC high dose amount, effective to increase the patient's morning plasma levels of cortisol to at least about 12 μg/dL, whereby said secondary adrenal insufficiency is treated, wherein the glucocorticoid receptor antagonist backbone is a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin.

2. The method of claim 1, wherein the patient is suspected of having secondary adrenal insufficiency after successful surgery for endogenous Cushing's syndrome.

3. The method of claim 1, wherein the patient is suspected of having secondary adrenal insufficiency after successful surgery of a pituitary ACTH-secreting tumor, an extra-adrenal cortisol secreting tumor, a unilateral hyperplastic adrenal gland associated with autonomous cortisol secretion, an ectopic ACTH secreting non-pituitary tumor, or a unilateral adrenocortical cortisol secreting tumor.

4. The method of claim 1, wherein the patient has not received glucocorticoid and glucocorticoid receptor antagonist treatment.

5. The method of claim 4, wherein the patient has not been treated for a disorder or condition selected from the group consisting of glaucoma, inflammatory diseases, rheumatoid arthritis, asthma and rhinitis, chronic pulmonary disease, allergies, and autoimmune diseases.

6. The method of claim 4, wherein the patient has not been treated to reduce a side effect of glucocorticoid treatment.

7. The method of claim 6, wherein the side effect is selected from the group consisting of weight gain, glaucoma, fluid retention, increased blood pressure, mood swings, cataracts, high blood sugar, diabetes, infection, loss of calcium from bones, osteoporosis, menstrual irregularities, fat redistribution, growth retardation, and cushingoid appearance.

8. The method of claim 1, wherein the glucocorticoid receptor antagonist is a selective inhibitor of the glucocorticoid receptor.

9. The method of claim 1, wherein the heteroaryl ketone fused azadecalin has the formula: ##STR00012## wherein R.sup.1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R.sup.1a; each R.sup.1a is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, CN, N-oxide, C.sub.3-8cycloalkyl, and C.sub.3-8 heterocycloalkyl; ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; each R.sup.2 is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, C.sub.1-6alkyl-C.sub.1-6alkoxy, CN, OH, NR.sup.2aR.sup.2b, C(O)R.sup.2a, C(O)OR.sup.2a, C(O)NR.sup.2aR.sup.2b, SR.sup.2a, S(O)R.sup.2a, S(O).sub.2R.sup.2a, C.sub.3-8cycloalkyl, and C.sub.3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R.sup.2c groups; alternatively, two R.sup.2 groups linked to the same carbon are combined to form an oxo group (═O); alternatively, two R.sup.2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R.sup.2d groups; R.sup.2a and R.sup.2b are each independently selected from the group consisting of hydrogen and C.sub.1-6 alkyl; each R.sup.2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, CN, and NR.sup.2aR.sup.2b; each R.sup.2d is independently selected from the group consisting of hydrogen and C.sub.1-6alkyl, or two R.sup.2d groups attached to the same ring atom are combined to form (═O); R.sup.3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R.sup.3a groups; each R.sup.3a is independently selected from the group consisting of hydrogen, halogen, and C.sub.1-6 haloalkyl; and subscript n is an integer from 0 to 3; or salts and isomers thereof.

10. The method of claim 1, wherein the octahydro fused azadecalin has the formula: ##STR00013## wherein R.sup.1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R.sup.1a; each R.sup.1a is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, N-oxide, and C.sub.3-8cycloalkyl; ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; each R.sup.2 is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, C.sub.1-6alkyl-C.sub.1-6alkoxy, CN, OH, NR.sup.2aR.sup.2b, C(O)R.sup.2a, C(O)OR.sup.2a, C(O)NR.sup.2aR.sup.2b, SR.sup.2a, S(O)R.sup.2a, S(O).sub.2R.sup.2a, C.sub.3-8cycloalkyl, and C.sub.3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S; alternatively, two R.sup.2 groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R.sup.2c groups; R.sup.2a, R.sup.2b and R.sup.2c are each independently selected from the group consisting of hydrogen and C.sub.1-6alkyl; each R.sup.3a is independently halogen; and subscript n is an integer from 0 to 3, or salts and isomers thereof.

11. The method of claim 1, wherein the glucocorticoid is selected from the group consisting of hydrocortisone, prednisone, dexamethasone, a glucocorticoid analogue, a synthetic glucocorticoid analogue, and derivatives thereof.

Description

III. EXAMPLES

Example 1: Case Report of Treating a Female Patient Suffering from Secondary Adrenal Insufficiency with a Glucocorticoid and a Glucocorticoid Receptor Antagonist

(1) The patient is a 39 year old woman who developed depression at the age of 20 for which she was placed on various psychotropic medications. At age 28, she developed progressive malaise, 25 pound weight gain, muscle weakness, easing bruising, hypertension and foot stress fracture. At age 31, she underwent screening DEXA bone density scan because of her personal history of fracture and a family history of advanced osteoporosis and genetically confirmed hypophosphotasia in her mother. The DEXA bone density scan disclosed a T-score of −3.4 at the lumbar spine and −3.1 at the hip. DNA sequencing of the ALPL (alkaline phosphatase, liver/bone/kidney) gene revealed no detectable disease-causing mutations. Further testing for secondary causes of osteoporosis included 24-hour urinary free cortisol which was markedly elevated at 499 mcg/day (range 10-80 mcg/day). Plasma ACTH level was undetectable. Adrenal imaging revealed a 3-cm right adrenal mass. At age 33, she underwent uncomplicated right laparoscopic adrenalectomy and histopathology confirmed a 3.7 cm adrenal cortical adenoma. The patient underwent a unilateral procedure, leaving one adrenal gland intact.

(2) Post-operatively the patient was placed on hydrocortisone replacement, initially at a dose of 40 mg/day given in divided doses and gradually tapered to 30 mg/day over the following several months. One year after her adrenalectomy, her hydrocortisone had been further tapered to 15 mg/day, which remained her maintenance dose.

(3) During the ensuing 6 years after her adrenalectomy, the patient generally felt unwell with symptoms of episodic nausea, headaches, lightheadedness, mood swings and generalized weakness. Quarterly measurement of serum cortisol and plasma ACTH levels (performed after holding hydrocortisone for 18 hours) consistently yielded undetectable values for both parameters. During this 6 year period, she had one pregnancy, occurring 3 years after adrenalectomy and progressing to full-term delivery of a healthy boy. She had two other hospitalizations (separated by 4 years) for near-syncope, malaise, nausea and vomiting (but without hypoglycemia or hypotension). Both episodes were treated with 48-hours of intravenous stress-doses of glucocorticoids and saline, followed by improvement of her symptoms and subsequent tapering of glucocorticoids to a replacement dose of hydrocortisone 15 mg/day.

(4) The failure of the HPA axis to recover six years after adrenalectomy (despite physiological steroid dosing) prompted magnetic resonance imaging of the sella to rule out structural abnormalities of the hypothalamus, infundibulum and pituitary. This MRI was unremarkable. At that time, after a balanced discussion of risk and benefit, mifepristone 150 mg every other day was initiated and the dose of hydrocortisone 15 mg/day was continued. Over the ensuing five months, the dose of mifepristone was gradually escalated to 300 mg every other day, then 300 mg daily and finally maintained at 600 mg daily. During this time, rapid recovery of the HPA axis was noted (initially with a rise, in ACTH into the supra-normal range 4-months after starting mifepristone, followed by a subsequent rise in cortisol levels). The dose of hydrocortisone was lowered and ultimately stopped 8 months after initiation of mifepristone. The patient tolerated mifepristone remarkably well; with the only side effects being amenorrhea and pruritis (she had a pre-existing history of urticaria). The pruritis was tolerable and managed with over the counter anti-histamines. At no point during treatment with mifepristone did the patient develop signs or symptoms of adrenal insufficiency. Her menses returned 3 weeks after discontinuation of mifepristone. Table 1 summarizes recovery of the HPA axis after initiation of mifepristone.

(5) TABLE-US-00001 TABLE 1 Drug Dosing Schedule and Response Month 0 1 3 4 5 6 8 10 11 Mife dose (mg) 0 150 300 300 600 600 300 0 0 TIW TIW daily daily daily TIW HC dose (mg) 15 15 15 15 15 10 0 0 0 ACTH (pg/mL) 5 15 18 60 78 173 126 26 45 Cortisol (ug/dL) <1 <1 <1 3.6 4.6 10.5 13.6 13.5 15.3 DHEA (ng/mL) <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.053 “Mife” denotes mifepristone. “HC” denotes hydrocortisone. “TIW” denotes three times per week.

(6) This example illustrates that a patient with second adrenal insufficiency was successfully treated by co-administration of hydrocortisone and mifepristone. Recovery of the patient's HPA axis was achieved. The patient's ACTH and cortisol levels increased in response to the drug treatment. Normal levels of ACTH and cortisol were maintained after completion of the treatment.

(7) The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible within the scope of the invention claimed. Moreover, any one or more features of any embodiment of the invention may be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.