Relugolix, sold under the brand names Orgovyx and Relumina and as one component of Myfembree, 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 cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

in men and uterine fibroids in women. It is also under development for use in the treatment of

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, ...

. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

once per day.

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of relugolix include menstrual abnormalities, hot flashes,

excessive sweating Hyperhidrosis is a condition characterized by abnormally increased sweating, in excess of that required for regulation of body temperature. Although primarily a benign physical burden, hyperhidrosis can deteriorate quality of life from a psychologi ...

headache Headache 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 in those with severe headaches. Headaches can occur as a resul ...

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

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 modulator 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 hormo ...

s, but similarly to elagolix (brand name Orilissa), relugolix is a non-peptide,

small-molecule Within the fields of 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 ar ...

compound and is

orally active Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

. 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 ...

levels to the postmenopausal or

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

range in both women and men with administration once per day. As of February 2019, relugolix is in phase III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for endometriosis. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020.

Medical uses

Relugolix is approved in the United States for the treatment of

in men and in Japan for the treatment of uterine fibroids (uterine leiomyoma) in women. It is used at a dosage of 120 mg once daily

in the treatment of prostate cancer (after a single 360 mg

loading dose In pharmacokinetics, a loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from ...

on the first day of therapy) and at a dosage of 40 mg once daily in the treatment of uterine fibroids.

Available forms

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

Side effects

The main

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s 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),

(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 antagonist of the

(GnRHR), with a

half-maximal inhibitory concentration The half maximal inhibitory concentration (IC50) is a measure of the Potency (pharmacology), potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particul ...

(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 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 (Gn ...

, 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, pubertal maturation, ...

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 sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

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 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 Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharm ...

of relugolix of 29 ng/mL (47 nmol/L) after 1.5 hours.

Steady-state levels Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

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%. ...

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 (locomotion), the surface over which an organism lo ...

for P-glycoprotein, which may have a limiting effect on its absorption 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 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. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from t ...

. 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 Feces ( or faeces), known colloquially and in slang as poo and poop, 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 large intestine. Feces contain a rela ...

(83%) and to a small degree in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

(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 analogues. It is an ''N''-

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydroge ...

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

History

Relugolix was first described in 2004. It superseded

sufugolix Sufugolix (, ) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) ( = 0.1 and 0.06 nM for affinity and ''in vitro'' inhibition, respectively). It ...

(developmental code name TAK-013), which was developed by the same researchers. Relugolix was approved for the treatment of uterine fibroids in Japan on 8 January 2019. It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (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

ethinyl estradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological diso ...

and

norethindrone Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both ...

is sold under the brand name Myfembree for the treatment of uterine fibroids.

Availability

Relugolix is available in the United States and in Japan.

Legal status

On 24 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. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Research

Relugolix is under development by Myovant Sciences and Takeda for the treatment of uterine fibroids in countries besides Japan such as the United States. Relugolix is also under development for the treatment of

in the United States and other countries.

References

External links

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