Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis

Abstract

Elagolix is a novel, oral gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose-dependent suppression of estradiol (E2) in clinical studies. A dose-response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen [CTX]), formation (N-terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in -0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

Trial registration: ClinicalTrials.gov NCT01620528 NCT01760954 NCT01931670 NCT02143713.

Conflict of interest statement

All authors are employees of AbbVie Inc. and may hold AbbVie stock and/or stock options.

© 2021 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Observed and model‐predicted estradiol levels in premenopausal women undergoing elagolix treatment. Observed (circles) and fitted (line) estradiol levels are shown. Daily dose is the total daily dose administered. The number of measurements (N) is represented by the size of the circle as noted in the legend. See Table 1 for study details. EM, endometriosis studies

FIGURE 2

Observations and QSP model predictions for changes in BMD and bone turnover biomarkers during treatment with elagolix for 6 and 12 months. Observed values are plotted as circles designated by study in the legend and correspond to month 6 (left panel) and month 12 (right panel). Observed data and study populations are denoted by N and are represented by the size of the circle. QSP model predictions are shown as a line. See Table 1 for source data and study information. BMD, bone mineral density; CTX, carboxyterminal cross‐linked telopeptide of type 1 collagen; P1NP, N‐terminal propeptide of type 1 procollagen; N, number of samples; QSP, quantitative systems pharmacology; EM, endometriosis studies

FIGURE 3

Observations and QSP model predictions of BMD and bone turnover biomarker changes during treatment and post‐treatment follow‐up periods in women treated with elagolix. BMD, CTX, and P1NP observations and model predictions are shown for the four treatment sequences that occurred across the endometriosis clinical studies and their respective extension studies. The left panel shows data for patients receiving placebo (plac) doses in EM‐1 or EM‐II who continued into their respective extension study (EM‐III or EM‐IV) and were randomized to receive either 150 mg once daily dose (150 q.d.) or 200 mg twice daily dose (200 b.i.d., e.g., plac/150 q.d./post and plac/200 b.i.d./post). The right panel shows data for patients who received either dosage and remained on the same dose into the extension study (e.g., 150 q.d./150 q.d./post and 200 b.i.d./200 b.i.d./post). Observed values are plotted as circles designated by study and respective extension study in the legend. The number of measurements is denoted by N and is represented by the size of the circle. BMD measurements were obtained every 6 months, whereas CTX and P1NP measurements were obtained every 3 months through the 12‐month clinical study and for an additional 6 months in the post‐treatment follow‐up period. The dotted line designates the start of treatment in the left panel, and the dashed line (second) indicates the end of treatment in both panels. See Table 1 for source data and study information. BMD, bone mineral density; CTX, carboxyterminal cross‐linked telopeptide of type 1 collagen; P1NP, N‐terminal propeptide of type 1 procollagen; QSP, quantitative systems pharmacology; EM, endometriosis studies

FIGURE 4

QSP model simulations of BMD changes during 12 months of elagolix treatment followed by a 12‐month follow‐up period. Dashed line indicates the end of elagolix treatment and the beginning of recovery. QSP, quantitative systems pharmacology; BMD, bone mineral density