Exposure-Safety Analyses Identify Predictors of Change in Bone Mineral Density and Support Elagolix Labeling for Endometriosis-Associated Pain

Ahmed Abbas Suleiman, Ahmed Nader, Insa Winzenborg, Denise Beck, Akshanth R Polepally, Juki Ng, Peter Noertersheuser, Nael M Mostafa, Ahmed Abbas Suleiman, Ahmed Nader, Insa Winzenborg, Denise Beck, Akshanth R Polepally, Juki Ng, Peter Noertersheuser, Nael M Mostafa

Abstract

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose-dependent manner. It is indicated for management of moderate-to-severe pain associated with endometriosis. A population exposure-response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis-associated pain. Elagolix pharmacokinetic exposure-dependent changes in BMD were described by an indirect-response maximum effect (Emax ) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type-I collagen C-telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in -1.45% (-2.04 to -0.814) decrease from baseline in BMD and were used to support corresponding dosing recommendations in the label.

Trial registration: ClinicalTrials.gov NCT01620528 NCT01931670 NCT01760954 NCT02143713.

Conflict of interest statement

AbbVie provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the abstract. A.A.S., A.N., I.W., D.B., A.R.P., J.N., P.N., and N.M.M. are AbbVie employees and may own stock.

© 2020 AbbVie Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Goodness‐of‐fit plots for the final exposure‐BMD model. Note: Individual predicted (IPRED; upper left) and population predicted (PRED; lower left) vs. observed (DV) lumbar spine bone mineral density (BMD) and conditional weighted residuals (CWRES) vs. population predicted lumbar spine BMD (upper right) and vs. time (lower right).
Figure 2
Figure 2
Visual predictive checks for the final exposure‐bone mineral density (BMD) model. M, month; FU, follow‐up. Note: Median (solid line), 5th, and 95th percentiles of the observed data (dashed lines) are compared to the 95% confidence intervals of the median, 5th, and 95th percentiles of the simulated data (shaded regions).
Figure 3
Figure 3
Simulated mean (95% confidence interval) for lumbar spine bone mineral density (BMD) % change over time for treatment with elagolix 150 mg q.d. for 24 months. Note: Solid line represents mean and shaded area represents 95% confidence interval of the mean.

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