Relugolix, sold under the brand names Orgovyx and Relumina among others, is a

gonadotropin-releasing hormone antagonist Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH). They are used in ...

(GnRH receptor antagonist) medication which is used in the treatment of

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

uterine fibroid Uterine fibroids, also known as uterine leiomyomas, fibromyoma or fibroids, are benign smooth muscle tumors of the uterus, part of the female reproductive system. Most people with fibroids have no symptoms while others may have painful or h ...

s and

endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of relugolix include menstrual abnormalities,

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es,

excessive sweating Hyperhidrosis is a medical condition in which a person exhibits excessive sweating, more than is required for the regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deteriorate the quality of life of the ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, and decreased bone mineral density. Relugolix is a GnRH antagonist, or an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.gonadotropin-releasing hormone receptor The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin- ...

. Unlike most other GnRH modulators, but similarly to

elagolix Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatme ...

(brand name Orilissa), relugolix is a non-peptide,

small-molecule In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; t ...

compound and is orally active. It suppresses

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

levels to the

postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

castrate Castration is any action, surgical, chemical, or otherwise, by which a male loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceutical d ...

range in both women and men.

Medical uses

Relugolix is approved in the United States, Canada and the United Kingdom for the treatment of

, in Japan for the treatment of

s (uterine leiomyoma) and in the United Kingdom for

Available forms

Relugolix is available in the form of 40 and 120 mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets.

Side effects

The main

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of relugolix for uterine fibroids include

abnormal uterine bleeding Abnormal uterine bleeding is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term "dysfunctional uterine bleeding" was used when no underlying cause was presen ...

(24.6–48.6% vs. 6.3% for placebo),

es (42.8–45.5% vs. 0% for placebo),

heavy menstrual bleeding Heavy menstrual bleeding (HMB), previously known as menorrhagia or hematomunia, is a menstruation, menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by stru ...

(12.1–49.3% vs. 9.4% for placebo),

(12.3–15.2%), and

(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).

Pharmacology

Pharmacodynamics

Estradiol levels with 40 mg per day oral relguolix therapy in premenopausal women

Relugolix is a selective

(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

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 Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

, and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

in premenopausal women. Relugolix at a dosage of 40 mg or more once per day has been found to reduce

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

levels to sustained

levels (<20 ng/dL) in men. 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

suppression in the treatment of endometriosis and uterine fibroids. This is intended to reduce the incidence and severity of

menopausal symptoms Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency.

Pharmacokinetics

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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of relugolix by about 50%. Relugolix is a

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

for

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

, which may have a limiting effect on its

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

and

distribution Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

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 Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

(83%) and to a small degree in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

(4%). Only about 6% of a dose of relugolix is excreted unchanged.

Chemistry

Relugolix is a non-peptide,

compound, and is structurally distinct from

GnRH analogue A GnRH modulator, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor modulator, is a type of medication which modulates the GnRH receptor, the biological target of the hypothalamic hormone gonadotropin-releasing horm ...

s. It is an ''N''-

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

History

Relugolix was first described in 2004. 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

(brand name Orilissa) in July 2018. 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.

Society and culture

Names

''Relugolix'' is the generic name of the drug and its , , and . 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. Relugolix compounded with estradiol hemihydrate and norethindrone is sold under the brand name Myfembree for the treatment of uterine fibroids.

Legal status

In February 2022, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

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. 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, Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. and in the United Kingdom in July 2022 (although not available in

NHS The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...

England until August 2024).

References

External links

* {{Portal bar , Medicine Dimethylamino compounds Ethers Fluoroarenes GnRH antagonists Hormonal antineoplastic drugs Pyridazines Pyrimidines Triketones Ureas