Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency.
BACKGROUND
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 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia.


METHODS
This was a phase 1 dose-escalation study.


METHODS
The study was conducted at university clinical research centers.


METHODS
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).


METHODS
AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate.


METHODS
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.


CONCLUSIONS
AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.
Division of Metabolism, Diabetes, and Endocrinology (R.J.A., E.O.B., G.D.H., C.R., D.M.), University of Michigan, Ann Arbor, Michigan 48109; Division of Endocrinology, Metabolism, Diabetes, and Nutrition (A.Y.C.), Mayo Clinic, Rochester, Minnesota 55905; Janssen Research and Development (G.W., M.G., X.S.X., J.J.), Raritan, New Jersey 08869; Janssen Research and Development (J.W.S.), 2340 Beerse, Belgium; and Janssen Research and Development (M.K.Y.), Los Angeles, California 90024.
Richard J
RJ
Auchus
Elizabeth O
EO
Buschur
Alice Y
AY
Chang
Gary D
GD
Hammer
Carole
C
Ramm
David
D
Madrigal
George
G
Wang
Martha
M
Gonzalez
Xu Steven
XS
Xu
Johan W
JW
Smit
James
J
Jiao
Margaret K
MK
Yu
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000069501:Abiraterone Acetate; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood* / Q000188:drug therapy*; D000328:Adult; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000728:Androgens / Q000097:blood*; D000730:Androstadienes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000735:Androstenedione / Q000097:blood / Q000652:urine; D000738:Androsterone / Q000031:analogs & derivatives / Q000652:urine; D003900:Desoxycorticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage; D016896:Treatment Outcome
D000726:Androgen Antagonists; D000728:Androgens; D000730:Androstadienes; C027927:androsterone glucuronide; D000735:Androstenedione; D003900:Desoxycorticosterone; D019326:17-alpha-Hydroxyprogesterone; D000738:Androsterone; D000069501:Abiraterone Acetate; D006854:Hydrocortisone