Assessment of Clinical Drug‐Drug Interactions of Elagolix, a Gonadotropin‐Releasing Hormone Receptor Antagonist

Akshanth R. Polepally, Juki Ng, Juki W Ng, Ahmed Hamed Salem, Matthew B Dufek, Apurvasena Parikh, David C Carter, Kent Kamradt, Nael M Mostafa, Mohamad Shebley
Journal of clinical pharmacology · 2020 · vol. 60(12) , pp. 1606–1616 · doi:10.1002/jcph.1689 · PMID:33045114 · PMC7689813 · W3040663058
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Abstract

Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by ∼2-fold following coadministration with ketoconazole and by ∼5- and ∼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.

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endometriosis

MeSH descriptors

Hydrocarbons, Fluorinated Hydrocarbons, Fluorinated Pyrimidines Pyrimidines Receptors, LHRH Adult ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP Binding Cassette Transporter, Subfamily G, Member 2 Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP2C9 Inhibitors

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