Ng Juki, Chwalisz Kristof, Carter David C, Klein Cheri E
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
General Medicine, AbbVie Inc., North Chicago, Illinois 60064.
J Clin Endocrinol Metab. 2017 May 1;102(5):1683-1691. doi: 10.1210/jc.2016-3845.
Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women.
We evaluated the pharmacokinetics and pharmacodynamics of elagolix.
DESIGN, SETTING, AND PARTICIPANTS: This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit.
Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days.
Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events.
Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush.
Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.
艾拉戈利是一种非肽类口服促性腺激素释放激素（GnRH）拮抗剂，正被开发用于治疗女性性激素依赖性疾病。
我们评估了艾拉戈利的药代动力学和药效学。
设计、地点和参与者：本研究是一项在研究单位对45名健康绝经前女性进行的随机、双盲、安慰剂对照、多剂量递增研究。
给予艾拉戈利[每日一次150毫克或每日两次（BID）100、200、300或400毫克]或安慰剂，持续21天。
主要观察指标为艾拉戈利的药代动力学、促性腺激素[促卵泡激素（FSH）、促黄体生成素（LH）]和卵巢激素[雌二醇（E2）、孕酮（P）]的抑制情况以及不良事件。
口服给药后，艾拉戈利迅速吸收，在1.0至1.5小时达到最大浓度，半衰期为4至6小时。在第1天，艾拉戈利给药数小时内FSH、LH和E2就受到抑制。观察到E2的抑制呈剂量依赖性，艾拉戈利每日两次200毫克时达到最大抑制。FSH和LH的抑制也呈剂量依赖性，分别在每日两次300毫克和每日两次200毫克时达到最大或接近最大抑制。在艾拉戈利剂量≥每日两次100毫克时，在整个21天的给药过程中P浓度维持在无排卵水平。最常报告的不良事件是头痛和潮热。
服用艾拉戈利可调节促性腺激素和卵巢激素浓度，从低剂量的部分抑制到高剂量的几乎完全抑制。本研究结果为艾拉戈利治疗女性性激素依赖性疾病的剂量选择提供了理论依据。
