Ketoconazole Effects on the Daily Cortisol Rhythm in Mild Autonomous Cortisol Secretion

Inclusion criteria

• To be eligible to participate in this study, an individual must meet all of the following criteria:
• Aged 18 years or older.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Agreement to adhere to Lifestyle Considerations throughout the study. A. Subjects with Mild Autonomous Cortisol Secretion (MACS):
• Co-enrollment in protocol 19DK0066.
• 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)
• One or more \>=1 cm adrenal nodule(s) on one or both adrenal glands on CT or MRI
• One normal 24-hour urine free cortisol value (per the reference range of the assay used).
• One morning plasma ACTH value \<10 pg/mL. B. Healthy volunteers:
• 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.
• 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)
• 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.
• 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:
• Inability to comply with all study procedures and visits.
• Inability of subject to understand or to sign a written informed consent document.
• Pregnancy or breastfeeding.
• 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.
• Use of medications within 2 weeks before inpatient admission that can block glucocorticoid production or action: ketoconazole (systemic), levoketoconazole, metyrapone, osilodrostat, mifepristone.
• 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.
• Anemia (hemoglobin \<13.7 g/dL for males, \<11.2 g/dL for females).
• Daily alcohol risk use (\>2 standard drinks per day by self-report during screening visit).
• Severely uncontrolled diabetes mellitus (HbA1c \>9.0%).
• Highly irregular sleep schedule in the week leading up to inpatient admission (e.g. shift work).
• Any contraindication to intravenous catheter use.
• Previous participation in this protocol.
• Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.
• 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):
• 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.
• 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.
• Known allergy or hypersensitivity to ketoconazole.
• Significant liver disease or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>3xULN, and/or total bilirubin \>1.5xULN during Screening.
• Prolonged QTc interval (\>500 msec) on screening ECG.
• 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.
• 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).