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

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.

• Authors: Ahmed Abbas Suleiman, Ahmed Nader, Insa Winzenborg, Denise Beck, Akshanth R Polepally, Juki Ng, Peter Noertersheuser, Nael M Mostafa
• Journal: CPT: pharmacometrics & systems pharmacology (CPT Pharmacometrics Syst Pharmacol) Vol. 9 Issue 11 Pg. 639-648 (11 2020) ISSN: 2163-8306 [Electronic] United States
• PMID: 32945631 (Publication Type: Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 AbbVie Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Collagen Type I
• Hydrocarbons, Fluorinated
• Peptides
• Pyrimidines
• Receptors, LHRH
• collagen type I trimeric cross-linked peptide
• elagolix

Topics

• Absorptiometry, Photon (methods)
• Administration, Oral
• Adult
• Black or African American (ethnology)
• Biological Variation, Population
• Body Mass Index
• Bone Density (drug effects)
• Case-Control Studies
• Collagen Type I (analysis)
• Computer Simulation
• Drug Labeling (standards)
• Endometriosis (complications)
• Female
• Humans
• Hydrocarbons, Fluorinated (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Middle Aged
• Pain (drug therapy, etiology)
• Peptides (analysis)
• Predictive Value of Tests
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Receptors, LHRH (antagonists & inhibitors)
• Safety