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Drug–Drug Interaction Studies of Elagolix with Oral and Transdermal Low-Dose Hormonal Add-Back Therapy

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Abstract

Background and Objective

Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-dose hormonal add-back therapy can reduce hypoestrogenic effects associated with elagolix, thus there is a need to determine if there is a pharmacokinetic interaction between elagolix and low-dose hormonal add-back therapy.

Methods

Two multiple-dose, open-label, single-sequence, non-randomized studies for elagolix 300 mg twice daily with oral (n = 24) and transdermal (n = 36) low-dose add-back therapy (estradiol [E2]/norethindrone acetate [NETA]; 1 mg/0.5 mg oral and 0.51 mg/4.8 mg transdermal) in healthy postmenopausal women were conducted, with pharmacokinetic sampling for E2, estrone (E1), and NETA up to 72 or 96 h after dosing. Pharmacokinetic parameters for hormones were estimated using noncompartmental methods.

Results

No change in norethindrone maximum plasma concentration or area under the concentration–time curve was observed when oral E2/NETA was administered with elagolix. For E2, there was a 2-fold increase in maximum plasma concentration and a 1.5-fold increase in the area under the concentration–time curve, and for E1 there was a 1.7-fold increase in maximum plasma concentration when oral E2/NETA was administered with elagolix. Exposures for norethindrone, E2, and E1 were unchanged when transdermal E2/NETA was applied with elagolix administration.

Conclusions

Although changes in E2/E1 exposures were observed when oral E2/NETA was co-administered with elagolix, these changes are not considered clinically relevant; and no dose adjustments are recommended when elagolix is co-administered with oral or transdermal low-dose add-back therapy.

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Availability of Data and Material

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Acknowledgments

The authors thank Mia DeFino, MS, ELS, a freelance medical writer under contract with AbbVie for medical writing support and Wesley Wayman, PhD, an AbbVie employee for assistance with the figures.

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Authors and Affiliations

  1. AbbVie Clinical Pharmacology and Pharmacometrics, 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Ahmed Nader, Nael M. Mostafa & Mohamad Shebley

  2. AbbVie Clinical Development, North Chicago, IL, USA

    Farah Ali

Authors
  1. Ahmed Nader
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  4. Mohamad Shebley
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AN. Data interpretation and manuscript writing was performed by all authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ahmed Nader.

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Funding

AbbVie funded the studies presented in this article. AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication.

Conflicts of Interest/Competing Interests

Ahmed Nader, Nael M. Mostafa, Farah Ali, and Mohamad Shebley are employees of AbbVie, Inc., and may own stocks or options.

Ethics approval

All studies were conducted in accordance with Good Clinical Practice guidelines and the ethical principles that have their origin in the Declaration of Helsinki. The protocols and informed consent forms were approved by the ethics committee or institutional review board at the site.

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All participants provided written informed consent for participation in the studies.

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All authors reviewed and approved the manuscript in the submitted form.

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Cite this article

Nader, A., Mostafa, N.M., Ali, F. et al. Drug–Drug Interaction Studies of Elagolix with Oral and Transdermal Low-Dose Hormonal Add-Back Therapy. Clin Pharmacokinet 60, 133–143 (2021). https://doi.org/10.1007/s40262-020-00921-y

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