relugolix

Relugolix is approved in the United States, Canada and the United Kingdom for the treatment of prostate cancer, in Japan for the treatment of uterine fibroids (uterine leiomyoma) and in the United Kingdom for endometriosis.{{Cite web |title=Relugolix - Myovant/Takeda |url=http://adisinsight.springer.com/drugs/800028257 |work=AdisInsight |publisher=Springer Nature Switzerland AG}}

Relugolix is available in the form of 40 and 120 mg oral tablets.

The main side effects of relugolix for uterine fibroids include abnormal uterine bleeding (24.6–48.6% vs. 6.3% for placebo), hot flashes (42.8–45.5% vs. 0% for placebo), heavy menstrual bleeding (12.1–49.3% vs. 9.4% for placebo), headache (12.3–15.2%), and excessive sweating (9.4–15.2% vs. 0% for placebo). In addition, decreased bone mineral density occurs with relugolix (21.7% decrease by week 12, 24.4% decrease by week 24).

File:Estradiol levels with 40 mg per day oral relguolix therapy in premenopausal women.png

Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR), with a half-maximal inhibitory concentration (IC₅₀) of 0.12 nM.

A dosage of relugolix of 40 mg once per day has been found to suppress estradiol levels to postmenopausal levels (<20 pg/mL) within 24 hours in premenopausal women. In the control group of women, estradiol levels fluctuated between 50 and 250 pg/mL. Estradiol levels have been found to return to normal concentrations within 4 weeks of discontinuation of relugolix in premenopausal women. The medication additionally suppresses levels of progesterone, luteinizing hormone, and follicle-stimulating hormone in premenopausal women. Relugolix at a dosage of 40 mg or more once per day has been found to reduce testosterone levels to sustained castrate levels (<20 ng/dL) in men.{{cite journal | vauthors = MacLean DB, Shi H, Faessel HM, Saad F | title = Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 12 | pages = 4579–4587 | date = December 2015 | pmid = 26502357 | pmc = 4667159 | doi = 10.1210/jc.2015-2770 }} It additionally suppresses luteinizing hormone and follicle-stimulating hormone levels in men.

Lower doses of relugolix (<40 mg/day) are under investigation for achieving partial sex hormone suppression in the treatment of endometriosis and uterine fibroids.{{cite journal |vauthors=Streuli I, de Ziegler D, Borghese B, Santulli P, Batteux F, Chapron C |date=March 2012 |title=New treatment strategies and emerging drugs in endometriosis |journal=Expert Opinion on Emerging Drugs |volume=17 |pages=83–104 |doi=10.1517/14728214.2012.668885 |pmid=22439891 |s2cid=27472695}} This is intended to reduce the incidence and severity of menopausal symptoms such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency.{{cite journal | vauthors = Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP | title = Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 2 | pages = 545–551 | date = February 2009 | pmid = 19033369 | pmc = 2646513 | doi = 10.1210/jc.2008-1695 }}

A single 40-mg oral dose of relugolix has been found to result in peak levels of relugolix of 29 ng/mL (47 nmol/L) after 1.5 hours. Steady-state levels are reached within 7 days with 40 mg/day relugolix administration. There is an approximate 2-fold accumulation of relugolix by 2 weeks of continuous administration. Food diminishes the oral bioavailability of relugolix by about 50%.

Relugolix is a substrate for P-glycoprotein, which may have a limiting effect on its absorption and distribution. The plasma protein binding of relugolix is approximately 68 to 71% over a concentration range of 0.05 to 5 μg/mL.

Relugolix is not a substrate for CYP3A4. The elimination half-life of relugolix is 36 to 65 hours across a dosage range of 20 to 180 mg/day. There is moderate to high interindividual variability in systemic exposure to relugolix.

Relugolix is excreted mainly in feces (83%) and to a small degree in urine (4%). Only about 6% of a dose of relugolix is excreted unchanged.

Relugolix is a non-peptide, small-molecule compound, and is structurally distinct from GnRH analogues.{{cite journal | vauthors = Tukun FL, Olberg DE, Riss PJ, Haraldsen I, Kaass A, Klaveness J | title = Recent Development of Non-Peptide GnRH Antagonists | journal = Molecules | volume = 22 | issue = 12 | pages = 2188 | date = December 2017 | pmid = 29232843 | pmc = 6149776 | doi = 10.3390/molecules22122188 | doi-access = free }} It is an N-phenyl urea derivative.

Relugolix was first described in 2004.{{Cite patent | country = US | number = 7300935 | url=https://patents.google.com/patent/US7300935 |title = Thienopyrimidine compounds and use thereof | inventor = Cho N, Imada T, Hitaka T, Miwa K, Kusaka M, Suzuki N | assign1 = Takeda Pharmaceutical Co Ltd | gdate = 27 November 2007 | postscript = . }} It superseded sufugolix (developmental code name TAK-013), which was developed by the same researchers. Relugolix was approved for the treatment of uterine fibroids in Japan in January 2019. It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (brand name Orilissa) in July 2018.{{Cite web | url=https://adisinsight.springer.com/drugs/800020238 | title=Elagolix - Abbvie/Neurocrine Biosciences | work = AdisInsight | publisher = Springer Nature Switzerland AG }} Relugolix was approved for the treatment of prostate cancer in the United States on 18 December 2020.

The FDA approved relugolix based on evidence from a clinical trial (NCT03085095) of 930 participants 48 to 97 years old with advanced prostate cancer. The trial was conducted at 155 sites in the United States, Canada, and countries in South America, Europe and the Asia Pacific region. All participants in the trial had advanced prostate cancer. Participants were randomly assigned to receive either one relugolix tablet daily (on the first day they received three tables) or an active control (leuprolide acetate) which was given as an injection under the skin every three months. The participants and healthcare providers were aware of which treatment was being given. The treatment lasted for 48 weeks. The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained low testosterone level equal to castration.{{cite web | title=Drug Trial Snapshot: Orgovyx | website=U.S. Food and Drug Administration (FDA) | date=18 December 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-orgovyx | access-date=6 January 2021}} {{PD-notice}}

Relugolix is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.{{Cite web | url=https://chem.nlm.nih.gov/chemidplus/rn/737789-87-6 | work = ChemIDplus | publisher = U.S. National Library of Medicine | title = Relugolix }}{{Cite web | url=https://www.kegg.jp/entry/D10888 | work = KEGG DRUG Database | publisher = Kyoto Encyclopedia of Genes and Genomes | title = Relugolix}} It is also known by its former developmental code names RVT-601 and TAK-385.

Relugolix is sold under the brand name Orgovyx for the treatment of prostate cancer and under the brand name Relumina for the treatment of uterine fibroids.{{Cite press release | url=https://www.prnewswire.com/news-releases/myovant-provides-corporate-updates-and-reports-financial-results-for-third-fiscal-quarter-ended-december-31-2018-300791994.html | title=Myovant Provides Corporate Updates and Reports Financial Results for Third Fiscal Quarter Ended December 31, 2018}} Relugolix compounded with estradiol hemihydrate and norethindrone is sold under the brand name Myfembree for the treatment of uterine fibroids.{{cite web | title=Myfembree- relugolix, estradiol hemihydrate, and norethindrone acetate tablet, film coated | website=DailyMed | date=18 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc3feb73-cc84-43a8-aa32-b262460495e8 | access-date=24 February 2024}}

In February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Orgovyx, intended for the treatment of prostate cancer. The applicant for this medicinal product is Myovant Sciences Ireland Limited.{{cite web | title=Orgovyx: Pending EC decision | website=European Medicines Agency | date=24 February 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/orgovyx | access-date=27 February 2022 | archive-date=27 February 2022 | archive-url=https://web.archive.org/web/20220227000205/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/orgovyx | url-status=dead }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Relugolix was approved for medical use in the European Union in April 2022,{{cite web | title=Orgovyx EPAR | website=European Medicines Agency | date=22 February 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/orgovyx | access-date=3 March 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.{{cite web | title=Orgovyx Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1642.htm | access-date=3 March 2023}} and in the United Kingdom in July 2022{{cite web | title=ORGOVYX FILM-COATED TABLETS RELUGOLIX - PLGB 00142/1272 | url=https://products.mhra.gov.uk/product/?product=ORGOVYX | access-date=20 September 2024 }} (although not available in NHS England until August 2024{{cite web | title=Relugolix for treating hormone-sensitive prostate cancer | url=https://www.nice.org.uk/guidance/TA995 | access-date=20 September 2024 }}).

{{Reflist}}

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• {{cite journal | vauthors = Markham A | title = Relugolix: First Global Approval | journal = Drugs | volume = 79 | issue = 6 | pages = 675–679 | date = April 2019 | pmid = 30937733 | doi = 10.1007/s40265-019-01105-0 | s2cid = 89616869 }}
• {{cite journal| vauthors = Elsharoud A, Ali M, Al-Hendy A |title=Relugolix. GnRH (LHRH) receptor antagonist, Treatment of uterine fibroids, Treatment of endometriosis-related pain, Treatment of prostate cancer|journal=Drugs of the Future|volume=44|issue=2|year=2019|pages=131|issn=0377-8282|doi=10.1358/dof.2019.44.2.2927590|s2cid=87369995}}
• {{cite journal | vauthors = Barra F, Seca M, Della Corte L, Giampaolino P, Ferrero S | title = Relugolix for the treatment of uterine fibroids | journal = Drugs of Today | volume = 55 | issue = 8 | pages = 503–512 | date = August 2019 | pmid = 31461087 | doi = 10.1358/dot.2019.55.8.3020179 | s2cid = 201654739 }}

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• {{ClinicalTrialsGov|NCT03085095|A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer (HERO)}}

{{Pituitary and hypothalamic hormones and analogues}}

{{GnRH and gonadotropins}}

{{GnRH and gonadotropin receptor modulators}}

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