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

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.

• Authors: Akshanth R Polepally, Juki W Ng, Ahmed Hamed Salem, Matthew B Dufek, Apurvasena Parikh, David C Carter, Kent Kamradt, Nael M Mostafa, Mohamad Shebley
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 60 Issue 12 Pg. 1606-1616 (12 2020) ISSN: 1552-4604 [Electronic] England
• PMID: 33045114 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 AbbVie Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Hydrocarbons, Fluorinated
• Liver-Specific Organic Anion Transporter 1
• Neoplasm Proteins
• Pyrimidines
• Receptors, LHRH
• SLCO1B1 protein, human
• Solute Carrier Organic Anion Transporter Family Member 1B3
• elagolix
• CYP2B6 protein, human
• CYP3A protein, human
• Cytochrome P-450 CYP2B6
• Cytochrome P-450 CYP3A

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (agonists, antagonists & inhibitors, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (metabolism)
• Adult
• Cytochrome P-450 CYP2B6 (metabolism)
• Cytochrome P-450 CYP2B6 Inducers (administration & dosage, pharmacokinetics)
• Cytochrome P-450 CYP2C9 Inhibitors (administration & dosage, pharmacokinetics)
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inducers (administration & dosage, pharmacokinetics)
• Cytochrome P-450 CYP3A Inhibitors (administration & dosage, pharmacokinetics)
• Drug Administration Schedule
• Drug Interactions
• Female
• Healthy Volunteers
• Humans
• Hydrocarbons, Fluorinated (administration & dosage, blood, pharmacokinetics, pharmacology)
• Liver-Specific Organic Anion Transporter 1 (antagonists & inhibitors, metabolism)
• Male
• Middle Aged
• Neoplasm Proteins (metabolism)
• Premenopause
• Pyrimidines (administration & dosage, blood, pharmacokinetics, pharmacology)
• Receptors, LHRH (antagonists & inhibitors)
• Solute Carrier Organic Anion Transporter Family Member 1B3 (antagonists & inhibitors, metabolism)
• Young Adult