Pharmacokinetic-Pharmacodynamic Modeling and Simulation of Merigolix, a Nonpeptide Gonadotropin-Releasing Hormone Antagonist

Gonadotropin-releasing hormone (GnRH) antagonists inhibit estrogen synthesis and secretion, making them promising treatment options for estrogen-dependent diseases, such as endometriosis. This study developed a population pharmacokinetic/pharmacodynamic (PK/PD) model for merigolix, a novel oral GnRH antagonist, to determine its optimal dosing in the treatment of endometriosis. Population PK/PD modeling was performed using NONMEM 7.4, incorporating data from phase I clinical studies involving single and multiple ascending dose (SAD and MAD) trials in healthy premenopausal volunteers. The PK profile was characterized using a two-compartment model incorporating first-order absorption and elimination processes. The temporal delay between merigolix concentration and subsequent estradiol (E2) suppression was described using an indirect response turnover model. The models were evaluated via visual predictive checks, goodness-of-fit plots, and bootstrap analysis. The PK model described merigolix concentrations across various doses (estimated clearance: 549 L/h, central volume of distribution: 1690 L). The PD model demonstrated dose-dependent E2 suppression (estimated maximum inhibitory effect [Imax]: 1, half-maximal inhibitory concentration [IC50]: 0.209 ng/mL). Simulations suggested that, assuming a baseline E2 concentration of 100 pg/mL, daily doses of 120 and 160 mg achieved the clinically meaningful target E2 range of 20–40 pg/mL (partial suppression), while higher doses of 240 and 320 mg resulted in target E2 levels below 20 pg/mL (full suppression), effectively controlling symptoms and minimizing the risk of bone mineral density loss. This PK/PD model provides a quantitative framework for optimizing merigolix dosing and supports the selection of dosing regimens for future clinical trials, potentially offering a novel therapeutic option for endometriosis treatment. Graphical abstract Similar content being viewed by others

Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–98. Maggi R, Cariboni AM, Marelli MM, Moretti RM, Andrè V, Marzagalli M, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update. 2016;22(3):358–81. 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. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75. Yang Q, Ciebiera M, Bariani MV, Ali M, Elkafas H, Boyer TG, et al. Comprehensive review of uterine fibroids: developmental origin, pathogenesis, and treatment. Endocr Rev. 2022;43(4):678–719. Dave D, Page HE, Carrubba AR. Clinical management of endometriosis in menopause: a narrative review. Medicina (Kaunas). 2024;60(8),1341. Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552–68. Constantin S, Bjelobaba I, Stojilkovic SS. Pituitary gonadotroph-specific patterns of gene expression and hormone secretion. Curr Opin Pharmacol. 2022;66:102274. Taylor HS, Dun EC, Chwalisz K. Clinical evaluation of the oral gonadotropin-releasing hormone-antagonist elagolix for the management of endometriosis-associated pain. Pain Manag. 2019;9(5):497–515. Oyola MG, Handa RJ. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress. 2017;20(5):476–94. 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. Ali M, A Rs A, Al Hendy A. Elagolix in the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Expert Rev Clin Pharmacol. 2021;14(4):427–37. Xin L, Ma Y, Ye M, Chen L, Liu F, Hou Q. Efficacy and safety of oral gonadotropin-releasing hormone antagonists in moderate-to-severe endometriosis-associated pain: a systematic review and network meta-analysis. Arch Gynecol Obstet. 2023;308(4):1047–56. Lamb YN. Elagolix: first global approval. Drugs. 2018;78(14):1501–8. 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. 2020;59(3):297–309. Beck D, Winzenborg I, Gao W, Mostafa NM, Chiuve SE, Owens C, et al. Interdisciplinary model-informed drug development for extending duration of elagolix treatment in patients with uterine fibroids. Br J Clin Pharmacol. 2022;88(12):5257–68. Relugolix, estradiol, and norethindrone acetate. Am J Health Syst Pharm. 2021;78(19):1755–60. Food and Drug Administration. Myfembree: clinical review (NDA 214846). [cited 2024 August 26]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214846Orig1s000MedR.pdf. Food and Drug Administration. Application number: 214846Orig1s000. Clinical pharmacology and biopharmaceutics review. [cited 2024 August 26]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214846Orig1s000ClinPharmR.pdf. Pohl O, Baron K, Riggs M, French J, Garcia R, Gotteland JP. A model-based analysis to guide gonadotropin-releasing hormone receptor antagonist use for management of endometriosis. Br J Clin Pharmacol. 2022;88(5):2359–71. Arjona Ferreira JC, Migoya E. Development of relugolix combination therapy as a medical treatment option for women with uterine fibroids or endometriosis. F&S Rep. 2023;4(2 Suppl):73–82. Keam SJ. Linzagolix: first approval. Drugs. 2022;82(12):1317–25. Kim SM, Yoo T, Lee SY, Kim EJ, Lee SM, Lee MH, et al. Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis. Life Sci. 2015;15(139):166–74. Han S, Cho YS, Yoon SK, Lim KS, Cho SH, Kim J, et al. First-in-human, double-blind, randomized controlled trial of an oral dose of GnRH antagonist TU2670 in healthy women. J Clin Endocrinol Metab. 2021;106(3):e1111–20. Hartner G, Husslein H, Kuessel L, Gstoettner M, Tiringer D, Wenzl R, et al. The latest advances in the pharmacological management of endometriosis. Expert Opin Pharmacother. 2023;24(1):121–33. Beck D, Winzenborg I, Liu M, Degner J, Mostafa NM, Noertersheuser P, et al. Population pharmacokinetics of elagolix in combination with low-dose estradiol/norethindrone acetate in women with uterine fibroids. Clin Pharmacokinet. 2022;61(4):577–87. Ho-Pham LT, Nguyen ND, Nguyen TV. Quantification of the relative contribution of estrogen to bone mineral density in men and women. BMC Musculoskelet Disord. 2013;23(14):366. Food and Drug Administration. Application number: 210450Orig1s000, Multi-discipline review. [cited 2024 August 26]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210450Orig1s000MultiD.pdf. Riggs MM, Bennetts M, van der Graaf PH, Martin SW. Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis. CPT Pharmacometr Syst Pharmacol. 2012;1(10):e11. Wu LS, Hu Y, Gane EJ, Slaets L, De Creus A, Ding Y, et al. Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants. Antivir Ther. 2023;28(1):13596535231151626. Bundgaard C, Larsen F, Jørgensen M, Mørk A. Pharmacokinetic/pharmacodynamic feedback modelling of the functional corticosterone response in rats after acute treatment with escitalopram. Basic Clin Pharmacol Toxicol. 2007;100(3):182–9. Gabrielsson J, Peletier LA. A flexible nonlinear feedback system that captures diverse patterns of adaptation and rebound. AAPS J. 2008;10(1):70–83. Food and Drug Administration. Application number: 214621Orig1s000, Center for Drug Evaluation and Research. [cited 2024 August 26]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/214621Orig1s000MultidisciplineR.pdf. Food and Drug Administration. Application number: 210450Orig1s000, ORILISSA label. [cited 2024 August 26]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210450Orig1s000Lbl.pdf. Neri M, Melis GB, Giancane E, Vallerino V, Pilloni M, Piras B, et al. Clinical utility of elagolix as an oral treatment for women with uterine fibroids: a short report on the emerging efficacy data. Int J Womens Health. 2019;11:535–46. Winzenborg I, Nader A, Polepally AR, Liu M, Degner J, Klein CE, et al. Population pharmacokinetics of elagolix in healthy women and women with endometriosis. Clin Pharmacokinet. 2018;57(10):1295–306. Shirley M. Relugolix: a review in advanced prostate cancer. Target Oncol. 2023;18(2):295–302. Lee TY, Pierrillas PB, Lin YW, de Greef R, Zandvliet AS, Schindler E, et al. Population PK and semimechanistic PK/PD modeling and simulation of relugolix effects on testosterone suppression in men with prostate cancer. Clin Pharmacol Ther. 2023;113(1):124–34. Muzii L, Galati G, Mercurio A, Olivieri C, Scarcella L, Azenkoud I, et al. Presurgical treatment of uterine myomas with the GnRH-antagonist relugolix in combination therapy: an observational study. Sci Rep. 2024;14(1):22481. Ali M, Chen HY, Chiang YF, Badary OA, Hsia SM, Al-Hendy A. An evaluation of relugolix/estradiol/norethindrone acetate for the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Expert Opin Pharmacother. 2022;23(4):421–9. Abbas Suleiman A, Nader A, Winzenborg I, Beck D, Polepally AR, Ng J, et al. Exposure-safety analyses identify predictors of change in bone mineral density and support elagolix labeling for endometriosis-associated pain. CPT Pharmacometr Syst Pharmacol. 2020;9(11):639–48. 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. 2020;59(5):617–27. Farkas S, Szabó A, Hegyi AE, Török B, Fazekas CL, Ernszt D, et al. Estradiol and estrogen-like alternative therapies in use: the importance of the selective and non-classical actions. Biomedicines. 2022;10(4),861. Funding This study was funded by a research grant from TiumBio, Seongnam, Republic of Korea. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of interest Soo Hyeon Bae, Jueun Kang, Sangil Jeon, Seon Mi Kim, Hun-Teak Kim, Seunghoon Han, and Sungpil Han declare that the research was carried out without any commercial or financial relationships that could be interpreted as a potential conflict of interest. Data availability statement The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval The study protocols were reviewed and approved by the Institutional Review Board at Asan Medical Center, Seoul and registered at ClinicalTrials.gov (NCT02202408). The protocol for the German cohort was reviewed and approved by the Ethics Committee of the Ärztekammer Nordrhein (EudraCT number: 2017-002558-35). The studies were performed at Asan Medical Center (Korea) and CRS Clinical Research Services Mannheim GmbH (Germany), and these were conducted in accordance with the 2013 Declaration of Helsinki (Fortaleza, Brazil) and the guidelines of the International Council for Harmonization Good Clinical Practice. Consent to participate All participants provided written informed consent prior to screening. Code availability Not applicable. Consent for publication Not applicable. Author contributions Sungpil Han developed the concepts and designed the experiments. Soohyeon Bae and Jueun Kang conducted the data analysis, PK/PD modeling, and simulation and wrote the paper. Sangil Jeon and Seunghoon Han analyzed the data throughout the study and provided valuable insights and guidance. Seon Mi Kim and Hun-Teak Kim designed and managed the clinical trials that provided the datasets for this modeling. 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 Bae, S.H., Kang, J., Jeon, S. et al. Pharmacokinetic–Pharmacodynamic Modeling and Simulation of Merigolix, a Nonpeptide Gonadotropin-Releasing Hormone Antagonist. Clin Pharmacokinet 65, 377–393 (2026). https://doi.org/10.1007/s40262-025-01595-0 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s40262-025-01595-0