Ketoconazole's effect on the daily cortisol rhythm in MACS

* INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all of the following criteria:

1. Aged 18 years or older.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Agreement to adhere to Lifestyle Considerations throughout the study.

A. Subjects with Mild Autonomous Cortisol Secretion (MACS):

1. Co-enrollment in protocol 19DK0066.
2. Abnormal low-dose overnight dexamethasone suppression test (morning serum cortisol \>1.8 mcg/dL following 1 mg oral dexamethasone between 2300-0000h the evening prior)
3. One or more \>=1 cm adrenal nodule(s) on one or both adrenal glands on CT or MRI
4. One normal 24-hour urine free cortisol value (per the reference range of the assay used).
5. One morning plasma ACTH value \<10 pg/mL.

B. Healthy volunteers:

1. In good general health as evidenced by medical history and physical examination; and in a stable state of health without ongoing acute/temporary illness per the clinical judgment of the investigator.
2. Normal low-dose overnight dexamethasone suppression test (morning serum cortisol \<=1.8 mcg/dL following 1 mg oral dexamethasone between 2300-0000h the evening prior)
3. Matching a participant with MACS who has completed testing in regard to:

   * Age: Birth year within 5 years of that of the participant with MACS.
   * Sex
   * BMI (kg/m2) category: \<18.5 (underweight); 18.5-24.9 (normal weight); 25-29.9 (overweight); 30-34.9 (obesity class 1); 35-39.9 (obesity class 2); \>=40 (obesity class 3).
   * For women: menopausal status as judged by absence of menses for one year and FSH\>15 mIU/mL.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Inability to comply with all study procedures and visits.
2. Inability of subject to understand or to sign a written informed consent document.
3. Pregnancy or breastfeeding.
4. Use of estrogen-containing oral contraceptives or oral estrogen therapy within 6 weeks before inpatient admission, due to possible increases in serum corticosteroid-binding globulin, and thereby total cortisol.
5. Use of medications within 2 weeks before inpatient admission that can block glucocorticoid production or action: ketoconazole (systemic), levoketoconazole, metyrapone, osilodrostat, mifepristone.
6. Use of oral, injectable, or inhaled glucocorticoids (unless intermittent, for symptomatic asthma) within the year before inpatient admission. Use of topical non-hydrocortisone containing potent glucocorticoids on more than 36 square inches within six months before inpatient admission.
7. Anemia (hemoglobin \<13.7 g/dL for males, \<11.2 g/dL for females).
8. Daily alcohol risk use (\>2 standard drinks per day by self-report during screening visit).
9. Severely uncontrolled diabetes mellitus (HbA1c \>9.0%).
10. Highly irregular sleep schedule in the week leading up to inpatient admission (e.g. shift work).
11. Any contraindication to intravenous catheter use.
12. Previous participation in this protocol.
13. Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.
14. Any hematology or chemistry screening laboratory value drawn at screening that the Investigator deems clinically significant for exclusion.

A. Subjects with Mild Autonomous Cortisol Secretion (MACS):

1. Evidence of hyperaldosteronism, which must have been ruled out with serum aldosterone and plasma renin activity measurements if the participant has a history of hypertension or hypokalemia, per standard clinical care.
2. Evidence of pheochromocytoma, which must have been ruled out with plasma or 24-hour urine metanephrines if an unenhanced adrenal nodule is \>10 HU, per standard clinical care.
3. Known allergy or hypersensitivity to ketoconazole.
4. Significant liver disease or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>3xULN, and/or total bilirubin \>1.5xULN during Screening.
5. Prolonged QTc interval (\>500 msec) on screening ECG.
6. Use of medications in the 2 weeks before inpatient admission that can:

   * Prolong QT when combined with ketoconazole (KTZ):

     \-- dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine.
   * Cause toxicity from increased concentration due to KTZ-induced CYP3A4 inhibition:

     --methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.
   * Inhibit CYP3A4 and increase KTZ bioavailability:

     \-- ritonavir, darunavir, fosamprenavir.
   * Induce CYP3A4 and decrease KTZ bioavailability:

     * Isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine.
7. Inability to pause, for 24 hours, use of medication that reduces KTZ absorption: proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole) and H2 antagonists (cimetidine, famotidine, nizatidine).

Inability to pause, for 3 hours, use of short-acting acid neutralizers that reduce KTZ absorption, e.g. aluminum hydroxide (acceptable if taken \>=1 hour before or \>=2 hours after KTZ).