Abiraterone Acetate to Lower Androgens in Women With Classic 21-Hydroxylase Deficiency

作者：Auchus Richard J^*; Buschur Elizabeth O; Chang Alice Y; Hammer Gary D; Ramm Carole; Madrigal David; Wang George; Gonzalez Martha; Xu Xu Steven; Smit Johan W; Jiao James; Yu Margaret K

来源：Journal of Clinical Endocrinology & Metabolism, 2014, 99(8): 2763-2770.

DOI：10.1210/jc.2014-1258

Context: Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer.
Objective: The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9 alpha-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia.
Design: This was a phase 1 dose-escalation study.
Setting: The study was conducted at university clinical research centers.
Participants: We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L).
Intervention: AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9 alpha-fludrocortisone acetate.
Main Outcome Measure: The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides.
Results: With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed.
Conclusion: AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.

• 出版日期2014-8