Development and Application of a Physiologically Based Pharmacokinetic Model for Elagolix in the Adult and Adolescent Population

Introduction Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis.

The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration.

Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14–18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals.

Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach. Similar content being viewed by others Change history 31 August 2024 A Correction to this paper has been published: https://doi.org/10.1007/s40262-024-01415-x

Surrey ES, Soliman AM, Agarwal SK, Snabes MC, Diamond MP. Impact of elagolix treatment on fatigue experienced by women with moderate to severe pain associated with endometriosis. Fertil Steril. 2019;112(2):298-304.e3. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, et al. Endometriosis. Endocr Rev. 2019;40(4):1048–79. Dinsdale N, Nepomnaschy P, Crespi B. The evolutionary biology of endometriosis. Evol Med Public Health. 2021;9(1):174–91. Donnez J, Dolmans M-M. GnRH antagonists with or without add-back therapy: a new alternative in the management of endometriosis? Int J Mol Sci. 2021;22(21):11342. Giudice LC. Endometriosis. N Engl J Med. 2010;362(25):2389–98. Liu Y-F, Fu S-Q, Yan Y-C, Gong B-B, Xie W-J, Yang X-R, et al. Progress in clinical research on gonadotropin-releasing hormone receptor antagonists for the treatment of prostate cancer. Drug Des Dev Ther. 2021;15:639–49. Lamb YN. Elagolix: first global approval. Drugs. 2018;78(14):1501–8. Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, Barnhart KT, Bradley LD, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328–40. Shebley M, Polepally AR, Nader A, Ng JW, Winzenborg I, Klein CE, et al. Clinical pharmacology of elagolix: an oral gonadotropin-releasing hormone receptor antagonist for endometriosis. Clin Pharmacokinet. 2019;59(3):297–309. Stodtmann S, Nader A, Polepally AR, Suleiman AA, Winzenborg I, Noertersheuser P, et al. Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis. Clin Transl Sci. 2021;14(4):1611–9. Carr BR, Stewart EA, Archer DF, Al-Hendy A, Bradley L, Watts NB, et al. Elagolix alone or with add-back therapy in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2018;132(5):1252–64. Surrey E, Taylor HS, Giudice L, Lessey BA, Abrao MS, Archer DF, et al. Long-term outcomes of elagolix in women with endometriosis. Obstet Gynecol. 2018;132(1):147–60. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(1):28–40. Wu W, Lin R, Ke M, Ye L, Lin C. Physiologically based pharmacokinetic modeling characterizes the drug–drug interaction between saxagliptin and rifampicin in patients with renal impairment. J Clin Pharmacol. 2023;63(7):848–58. Zhu J, Zhou S, Wang L, Zhao Y, Wang J, Zhao T, et al. Characterization of pediatric rectal absorption, drug disposition, and sedation level for midazolam gel using physiologically based pharmacokinetic/pharmacodynamic modeling. Mol Pharm. 2024;21(5):2187–97. Khalid S, Rasool MF, Masood I, Imran I, Saeed H, Ahmad T, et al. Application of a physiologically based pharmacokinetic model in predicting captopril disposition in children with chronic kidney disease. Sci Reports. 2023;13(1): 29798. Zhu J, Zhao Y, Wang L, Zhou C, Zhou S, Chen T, et al. Physiologically based pharmacokinetic/pharmacodynamic modeling to evaluate the absorption of midazolam rectal gel. Eur J Pharm Sci. 2021;167: 106006. Zhao H, Wei Y, He K, Zhao X, Mu H, Wen Q. Prediction of janagliflozin pharmacokinetics in type 2 diabetes mellitus patients with liver cirrhosis or renal impairment using a physiologically based pharmacokinetic model. Eur J Pharm Sci. 2022;179: 106298. Mukherjee D, Chen M-J, Shao X, Ju TR, Shebley M, Marroum P. Virtual bioequivalence assessment of elagolix formulations using physiologically based pharmacokinetic modeling. AAPS J. 2023;25(3):00794. Chiney MS, Ng J, Gibbs JP, Shebley M. Quantitative assessment of elagolix enzyme-transporter interplay and drug–drug interactions using physiologically based pharmacokinetic modeling. Clin Pharmacokinet. 2019;59(5):617–27. Ng J, Duan WR, Marbury T, Schmidt JM, Klein CE. Elagolix pharmacokinetic profiles in women with renal or hepatic impairment. Clin Pharmacol Drug Dev. 2018;8(8):1053–61. Gouju J, Legeay S. Pharmacokinetics of obese adults: Not only an increase in weight. Biomed Pharm. 2023;166: 115281. Miedema MD, Maziarz M, Biggs ML, Zieman SJ, Kizer JR, Ix JH, et al. Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the cardiovascular health study). Am J Cardiol. 2014;114(6):843–8. Falcone T, Flyckt R. Clinical management of endometriosis. Obstet Gynecol. 2018;131(3):557–71. Martone S, Marcolongo P, Luisi S. Role of medical treatment of endometriosis. Minerva Obstet Gynecol. 2021;73(3):304–16. Schneider MP, Vitonis AF, Fadayomi AB, Charlton BM, Missmer SA, DiVasta AD. Quality of life in adolescent and young adult women with dyspareunia and endometriosis. J Adolesc Health. 2020;67(4):557–61. Jebeile H, Kelly AS, O’Malley G, Baur LA. Obesity in children and adolescents: epidemiology, causes, assessment, and management. Lancet Diabetes Endocrinol. 2022;10(5):351–65. Lister NB, Baur LA, Felix JF, Hill AJ, Marcus C, Reinehr T, et al. Child and adolescent obesity. Nat Rev Dis Primers. 2023;9(1):00435. Smit C, De Hoogd S, Brüggemann RJM, Knibbe CAJ. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. Expert Opin Drug Metab Toxicol. 2018;14(3):275–85. Zarezadeh M, Saedisomeolia A, Shekarabi M, Khorshidi M, Emami MR, Müller DJ. The effect of obesity, macronutrients, fasting and nutritional status on drug-metabolizing cytochrome P450s: a systematic review of current evidence on human studies. Eur J Nutr. 2020;60(6):2905–21. Acknowledgment The authors thank the volunteers for their participation and cooperation. We would like to thank Editage (www.editage.cn) for English language editing. Appreciation to the technical engineer Wang Yuxi from Shanghai PharmGO Company for the technical support provided. Author information Authors and Affiliations Corresponding authors Ethics declarations Funding This study was funded by Science and technology development plan of Jinan Health Commission (2024), Jinan Technology Development Program, China (Grant No. 202134049) and Shandong Province Medical and Health Technology Project (202313010781). Conflict of interest Xinghai Zhang, Xuanxuan Wang, Rui Li, Chenning Zhang, Jianmin Du, Hengli Zhao, and Qing Wen declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Author contributions Xinghai Zhang and Hengli Zhao wrote the manuscript. Xuanxuan Wang and Rui Li acquired, analyzed and interpreted the data. Xinghai Zhang, Jianmin Du and Chenning Zhang built the model. Qing Wen and Hengli Zhao designed the study. All authors read and approved the final manuscript. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author (Qing Wen) on reasonable request. Ethical Approval Some of the data in this study were derived from clinical trials conducted at our center. The clinical trial was reviewed and approved by the Ethics Committee of the Central Hospital Affiliated to Shandong First Medical University (Jinan, China). Code availability Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Additional information The original online version of this article was revised to include the co-corresponding author and the revised supplementary file. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Zhang, X., Wang, X., Li, R. et al. Development and Application of a Physiologically Based Pharmacokinetic Model for Elagolix in the Adult and Adolescent Population. Clin Pharmacokinet 63, 1357–1370 (2024). https://doi.org/10.1007/s40262-024-01402-2 Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s40262-024-01402-2