Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
Pharmacogenetics, AbbVie, North Chicago, IL, USA.
Clin Pharmacokinet. 2022 Apr;61(4):577-587. doi: 10.1007/s40262-021-01096-w. Epub 2021 Dec 8.
Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids.
Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach.
Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids.
Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids.
ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).
Elagolix 是一种口服活性、促性腺激素释放激素受体拮抗剂，已被批准用于治疗子宫内膜异位症相关疼痛和与子宫肌瘤相关的重度月经过多。此前已有研究报道了 Elagolix 在健康女性和子宫内膜异位症女性中的群体药代动力学及影响 Elagolix 暴露的因素。本研究的目的是扩展群体药代动力学模型，增加一些修改，以纳入 Elagolix 联合激素添加治疗子宫肌瘤女性的三项 III 期研究的数据。
共纳入 13 项临床研究（共 2168 名女性）的数据，包括 6 项健康绝经前女性的 I 期研究、4 项绝经前子宫内膜异位症女性的 III 期研究和 3 项绝经前子宫肌瘤女性的 III 期研究，采用非线性混合效应模型进行分析。
Elagolix 的群体药代动力学特征最好用一个两室模型描述，该模型具有一级吸收、吸收时滞和一级消除。在对 Elagolix 表观清除率、表观分布容积和/或相对生物利用度进行的所有候选协变量检验中，只有有机阴离子转运多肽 1B1 基因型和体重对 Elagolix 的相对生物利用度和表观分布容积有统计学意义但无临床意义的影响。在健康女性、子宫内膜异位症女性或子宫肌瘤女性中，Elagolix 的群体药代动力学无临床意义的差异。
Elagolix 的群体药代动力学模型未发现任何与患者相关的因素或临床参数，因此无需调整批准剂量（每日两次 300mg，同时联用 1mg 雌二醇/0.5mg 醋酸炔诺酮），用于治疗与子宫肌瘤相关的重度月经过多的女性。
ClinicalTrials.gov 标识符：NCT01620528（EM-1）、NCT01760954（EM-1-Extend）、NCT01931670（EM-2）、NCT02143713（EM-2-Extend）、NCT02654054（UF-1）、NCT02691494（UF-2）、NCT0295494（UF-Extend）。
