Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency

Autor: Adina F. Turcu, Tim Muth, Richard J. Auchus, Carole A. Ramm, Robert Farber, Dimitri E. Grigoriadis, Rosa Luo, David Madrigal, Christopher F. O'Brien, Joanna L. Spencer-Segal
Rok vydání: 2016
Předmět:
Adult
0301 basic medicine
medicine.medical_specialty
Time Factors
medicine.drug_class
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
030209 endocrinology & metabolism
Adrenocorticotropic hormone
Pharmacology
Receptors
Corticotropin-Releasing Hormone
Biochemistry
Young Adult
03 medical and health sciences
Corticotropin-releasing hormone
0302 clinical medicine
Endocrinology
Adrenocorticotropic Hormone
Internal medicine
medicine
Humans
Androstenedione
Hydrocortisone
Oxadiazoles
Adrenal Hyperplasia
Congenital
Dose-Response Relationship
Drug
business.industry
17-alpha-Hydroxyprogesterone
Biochemistry (medical)
Corticotropin-Releasing Factor Receptor 1
Antagonist
Original Articles
Middle Aged
Receptor antagonist
030104 developmental biology
Tolerability
Female
business
Azabicyclo Compounds
medicine.drug
Zdroj: The Journal of Clinical Endocrinology & Metabolism. 101:1174-1180
ISSN: 1945-7197
0021-972X
Popis: Context: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. Objectives: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. Participants: The study enrolled eight classic 21OHD females, ages 18–58 years, seen at a single tertiary referral university setting. Design: This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. Results: Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. Conclusion: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.
Databáze: OpenAIRE
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