Population Pharmacokinetics of Elagolix in Combination with Low-Dose Estradiol/Norethindrone Acetate in Women with Uterine Fibroids

Abstract

Background and objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinical trial registration: 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).

Trial registration: ClinicalTrials.gov NCT01620528 NCT01760954 NCT01931670 NCT02143713 NCT02654054 NCT02691494 NCT02925494.

Conflict of interest statement

DB, IW, ML, JD, NMM, PN, and MS are employees of AbbVie Inc. and may hold AbbVie stock and/or stock options.

© 2021. The Author(s).

Figures

Fig. 1

Covariate relationships in healthy women and patients. a Elagolix apparent clearance and b elagolix apparent central volume of distribution. In the figure, the box shows the interquartile range with a median line. Lower/upper whiskers extend to the lowest/highest value within the 1.5× interquartile range. Data beyond the end of the whiskers are shown as filled circles

Fig. 2

Goodness-of-fit plots for the final population-pharmacokinetic model. a Population-predicted elagolix concentrations vs observed concentrations; b individual-predicted elagolix concentrations vs observed concentrations; c conditional weighted residuals vs time; and d conditional weighted residuals vs population predictions. Note: goodness-of-fit plots showing conditional weighted residuals are cut off at − 6 to 6, resulting in two data points not shown in the plot. EM endometriosis, UF uterine fibroids

Fig. 3

Visual predictive checks for the final population-pharmacokinetic model. a phase I; b phase III, patients with endometriosis; and c phase III, patients with uterine fibroids. Note: visual predictive checks are cut off at 30 h after the last dose, as data are too sparse beyond. The gray dots represent observed data, the lines represent observed median (solid orange) and observed 5th and 95th percentiles (dashed orange), and the shaded blue regions represent the 90% prediction intervals for the simulated median and 5th and 95th percentiles (solid blue)

Fig. 4

Effects of organic anion transporting polypeptide (OATP) 1B1 genotype status and body weight on elagolix average plasma concentration. Effects were determined following an elagolix dose of 300 mg twice daily. Dots and error bars represent median and 5th and 95th percentiles for simulated ratios of elagolix average concentrations stratified by covariate subgroup