Top

Published in:

01-10-2018 | Original Research Article

Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis

Authors: Insa Winzenborg, Ahmed Nader, Akshanth R. Polepally, Mohan Liu, Jacob Degner, Cheri E. Klein, Nael M. Mostafa, Peter Noertersheuser, Juki Ng

Published in: Clinical Pharmacokinetics | Issue 10/2018

Abstract

Introduction

Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters.

Methods

The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis.

Results

Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F.

Conclusion

Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis.

Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

Available only for authorised users

Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20(10):2698–704.CrossRefPubMed

Viganò P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177–200.CrossRefPubMed

Facchin F, Barbara G, Saita E, et al. Impact of endometriosis on quality of life and mental health: pelvic pain makes the difference. J Psychosom Obstet Gynaecol. 2015;36(4):135–41.CrossRefPubMed

Struthers RS, Chen T, Campbell B, et al. Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI-42902). J Clin Endocrinol Metab. 2006;91(10):3903–7.CrossRefPubMed

Struthers RS, Nicholls AJ, Grundy J, et al. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab. 2009;94(2):545–51.CrossRefPubMed

Ng J, Chwalisz K, Carter DC, Klein CE. Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women. J Clin Endocrinol Metab. 2017;102(5):1683–91.CrossRefPubMed

Carr B, Dmowski WP, O’Brien C, et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014;21(11):1341–51.CrossRefPubMedPubMedCentral

Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40.CrossRefPubMed

Surrey E, Taylor HS, Giudice LC, et al. Long-term safety and efficacy of elagolix treatment in women with endometriosis-associated pain: primary results from two phase 3 extension studies [abstract no. O-233]. Fertil Steril. 2017;108(3 Suppl):e95–6.CrossRef

10.

Archer D, Ng J, Chiu Y-L, Klein C, Chwalisz K. Dose-dependent suppression of ovulation and ovarian activity by elagolix in healthy premenopausal women. Society for Reproductive Investigation (SRI) 64th annual meeting, 15–18 Mar 2017, Orlando.

11.

Ng J, Chiu Y-L, Chwalisz K, Klein C. Effects of elagolix, an oral gonadotropin-releasing hormone (GnRH), on gonadotropins and ovarian sex hormones in healthy premenopausal women [poster no. PS02-003]. World Congress on Endometriosis (WCE), 17–20 May 2017, Vancouver.

12.

Ng J, Archer D, Chiu Y-L, Klein C, Chwalisz K. Effects of elagolix, an oral gonadotropin-releasing hormone (GnRH), on ovulation, ovarian activity, and ovarian reserve in healthy premenopausal women [poster no. PS02-004]. World Congress on Endometriosis (WCE), 17–20 May 2017, Vancouver.

13.

Chen C, Wu D, Guo Z, et al. Discovery of sodium r-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2h-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2008;51(23):7478–85.CrossRefPubMed

14.

Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: Phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447(5):653–65.CrossRefPubMed

15.

Ng J, Salem AH, Carter D, Williams LA, Klein CE. Effects of the coadministration of single and multiple doses of rifampin on the pharmacokinetics and safety of elagolix in healthy premenopausal females [poster no. PI-089]. American Society for Clinical Pharmacology and Therapeutics (ASCPT), 8–12 Mar 2016, San Diego.

16.

Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.CrossRefPubMedPubMedCentral

Title: Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis
Authors: Insa Winzenborg
Ahmed Nader
Akshanth R. Polepally
Mohan Liu
Jacob Degner
Cheri E. Klein
Nael M. Mostafa
Peter Noertersheuser
Juki Ng
Publication date: 01-10-2018
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 10/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-018-0629-6

ACC 2024 Congress

Springer Medicine

Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis

Abstract

Introduction

Methods

Results

Conclusion

ACC 2024 Congress

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 10/2018

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

Predictive Performance of Physiologically-Based Pharmacokinetic Models in Predicting Drug–Drug Interactions Involving Enzyme Modulation

Complex Drug–Drug–Gene–Disease Interactions Involving Cytochromes P450: Systematic Review of Published Case Reports and Clinical Perspectives

Polymorphic Expression of UGT1A9 is Associated with Variable Acetaminophen Glucuronidation in Neonates: A Population Pharmacokinetic and Pharmacogenetic Study

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

Author’s Reply to Reith: “Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults”