单剂量促肾上腺皮质激素释放因子受体-1拮抗剂对 21-羟化酶缺乏症女性的研究

Journal of the Royal Statistical Society Pub Date : 2016-03-01 Epub Date: 2016-01-11 DOI:10.1210/jc.2015-3574
Adina F Turcu, Joanna L Spencer-Segal, Robert H Farber, Rosa Luo, Dimitri E Grigoriadis, Carole A Ramm, David Madrigal, Tim Muth, Christopher F O'Brien, Richard J Auchus
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引用次数: 0

摘要

背景:21-羟化酶缺乏症(21OHD)的治疗难以优化。要使过多的促肾上腺皮质激素(ACTH)和肾上腺类固醇分泌正常化,通常需要超生理剂量的糖皮质激素:我们评估了选择性促肾上腺皮质激素释放因子1型(CRF1)受体拮抗剂NBI-77860在典型21OHD女性患者中的安全性和耐受性,并检验了CRF1受体阻断可降低这些患者清晨促肾上腺皮质激素和17α-羟孕酮(17OHP)的假设:该研究招募了 8 名典型的 21OHD 女性患者,年龄在 18-58 岁之间,均在一所三级转诊大学就诊:这是一项 Ib 期、单盲、安慰剂对照、固定顺序、单剂量试验。在间隔 3 周的三个治疗期内,患者依次接受安慰剂、NBI-77860 300 毫克和 NBI-77860 600 毫克的治疗,时间为晚上 10 点;糖皮质激素治疗暂停 20 小时。我们对 24 小时内的促肾上腺皮质激素、17OHP、雄烯二酮和睾酮以及 NBI-77860 药代动力学进行了评估:结果:在八名受试者中,有六名受试者的促肾上腺皮质激素和/或 17OHP 出现了剂量依赖性下降。与安慰剂相比,300 毫克剂量的 NBI-77860 可使促肾上腺皮质激素和 17OHP 平均分别降低 43% 和 0.7%,600 毫克剂量的 NBI-77860 可使促肾上腺皮质激素和 17OHP 平均分别降低 41% 和 27%。两种剂量的NBI-77860都具有良好的耐受性:结论:21OHD患者服用NBI-77860后,促肾上腺皮质激素(ACTH)和17OHP明显减少,这表明该药物可用于该疾病的靶点,并证明了其原理。这些令人鼓舞的数据为进一步研究在生理剂量氢化可的松和醋酸氟氢可的松基础上添加 CRF1 受体拮抗剂治疗典型的 21OHD 提供了依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency.

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.

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