Clinical Pharmacology and Pharmacometrics, Department R4PK, AbbVie Inc., Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Clin Pharmacokinet. 2018 Oct;57(10):1295-1306. doi: 10.1007/s40262-018-0629-6.
Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters.
The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis.
Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F.
Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.
Elagolix 是一种新型的、口服活性的、非肽类、竞争性促性腺激素释放激素（GnRH）受体拮抗剂，目前正在开发用于治疗与子宫纤维瘤相关的子宫内膜异位症相关疼痛和月经过多。Elagolix 的药代动力学在 I 期研究中得到了很好的描述；然而，之前没有报告过 Elagolix 的群体药代动力学。因此，建立了一个强大的模型来描述 Elagolix 的群体药代动力学，并评估影响 Elagolix 药代动力学参数的因素。
来自 9 项临床研究（共 1624 名女性）的数据被纳入分析：5 项 I 期研究在健康的绝经前妇女中进行，4 项 III 期研究在患有子宫内膜异位症的绝经前妇女中进行。
Elagolix 的群体药代动力学最好用一个两室模型来描述，该模型具有吸收的滞后时间。在测试对 Elagolix 表观清除率（CL/F）和/或分布容积有影响的 15 个协变量中，只有一个协变量——有机阴离子转运蛋白 1B1（OATP1B1）基因型状态，对 Elagolix CL/F 有统计学意义但无临床意义的影响。
Elagolix 的药代动力学不受患者人口统计学特征的影响，且在健康女性和子宫内膜异位症女性中相似。临床试验注册号：NCT01403038、NCT01620528、NCT01760954、NCT01931670、NCT02143713。
