Relugolix

Identification

Summary

Relugolix is an oral GnRH receptor antagonist for androgen deprivation therapy in the treatment of advanced prostate cancer.

Brand Names
Myfembree, Orgovyx
Generic Name
Relugolix
DrugBank Accession Number
DB11853
Background

Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist used in the treatment of several hormone-responsive conditions. It was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids,6 and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer.9,10 Relugolix has also been studied in the symptomatic treatment of endometriosis.1

Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer - similar therapies such as degarelix require subcutaneous administration - and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals.10 In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer.8 In May 2021, the FDA approved the combination product made up of relugolix, estradiol, and norethindrone under the market name Myfembree for the first once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.12

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 623.64
Monoisotopic: 623.176244497
Chemical Formula
C29H27F2N7O5S
Synonyms
  • Relugolix
External IDs
  • TAK 385
  • TAK-385

Pharmacology

Indication

Relugolix is indicated for the treatment of adult patients with advanced prostate cancer.9 In a combination product with estradiol and norethindrone, relugolix is indicated for the once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.12

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Approximately 56% of patients achieved castrate-level testosterone concentrations (<50 ng/dL) by day 4 of therapy and 97% of patients maintain these levels through 48 weeks of therapy.9 Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations.

Androgen deprivation therapies may prolong the QTc interval and should therefore be used with caution in patients having a high baseline risk of QTc prolongation, such as those with electrolyte abnormalities, congestive heart failure, or using other medications known to prolong the QTc interval.9 Based on its mechanism of action and data from animal studies, relugolix may result in fetal harm if administered to pregnant females - male patients with female partners should be advised to use effective contraception throughout therapy and for 2 weeks following cessation of therapy to prevent inadvertent fetal exposure.9

Mechanism of action

The pathogenesis and progression of prostate cancer appear driven, at least in part, by the effects of testosterone.5 Androgen deprivation has been demonstrated to result in cell death and tumor regression in many well-differentiated prostate cancer cell lines - for this reason, androgen deprivation therapy (ADT) has become a standard in the treatment of prostate cancer, particularly in advanced disease.

Testosterone production in males is carried out in the Leydig cells of testes and is stimulated by luteinizing hormone (LH), which itself is produced in the pituitary gland following the binding of gonadotropin-releasing hormone (GnRH) to corresponding GnRH receptors.11 Relugolix is a competitive antagonist of these GnRH receptors, thereby decreasing the release of LH and, ultimately, testosterone.9

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Humans
Absorption

The Cmax and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the Cmax increases greater than proportionally to the dose.9 Following the administration of 120mg once daily, the steady-state AUC and Cmax of relugolix were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively.

The absolute oral bioavailability of relugolix is approximately 12% and the median Tmax following oral administration is 2.25 hours.9

Volume of distribution

Not Available

Protein binding

Relugolix is 68-71% protein-bound in plasma, primarily to albumin and, to a lesser extent, α1-acid glycoprotein.9

Metabolism

Relugolix is metabolized mainly by the CYP3A subfamily of P450 enzymes, with a smaller contribution by CYP2C8.9

Route of elimination

Approximately 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained unchanged.9

Half-life

The average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours.9

Clearance

The average renal clearance of relugolix is 8 L/h with a total clearance of 26.4 L/h.9

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdose of relugolix are unavailable.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Relugolix can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Relugolix can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Relugolix.
AbirateroneThe metabolism of Relugolix can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Relugolix can be decreased when combined with Acalabrutinib.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Relugolix.
AdalimumabThe metabolism of Relugolix can be increased when combined with Adalimumab.
AdenosineThe risk or severity of QTc prolongation can be increased when Relugolix is combined with Adenosine.
AfatinibThe serum concentration of Relugolix can be increased when it is combined with Afatinib.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Relugolix.
Interactions
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Food Interactions
  • Take with or without food. Administration with food does not result in any clinically meaningful differences in pharmacokinetics.

Products

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International/Other Brands
Orgovyx / Relumina
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OrgovyxTablet, film coated120 mg/1OralMyovant Sciences, Inc.2020-12-18Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
MyfembreeRelugolix (40 mg/1) + Estradiol hemihydrate (1 mg/1) + Norethisterone acetate (0.5 mg/1)Tablet, film coatedOralMyovant Sciences, Inc.2021-05-26Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-phenylureas. These are compounds containing a N-phenylurea moiety, which is structurally characterized by a phenyl group linked to one nitrogen atom of a urea group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
N-phenylureas
Direct Parent
N-phenylureas
Alternative Parents
Thienopyrimidines / Pyrimidones / Alkyl aryl ethers / Aralkylamines / Fluorobenzenes / Pyridazines and derivatives / Aryl fluorides / Vinylogous amides / Thiophenes / Heteroaromatic compounds
show 8 more
Substituents
Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Carbonyl group / Ether / Fluorobenzene
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
P76B05O5V6
CAS number
737789-87-6
InChI Key
AOMXMOCNKJTRQP-UHFFFAOYSA-N
InChI
InChI=1S/C29H27F2N7O5S/c1-36(2)14-19-24-26(39)38(22-12-13-23(42-3)34-33-22)29(41)37(15-18-20(30)6-5-7-21(18)31)27(24)44-25(19)16-8-10-17(11-9-16)32-28(40)35-43-4/h5-13H,14-15H2,1-4H3,(H2,32,35,40)
IUPAC Name
1-(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1H,2H,3H,4H-thieno[2,3-d]pyrimidin-6-yl}phenyl)-3-methoxyurea
SMILES
CONC(=O)NC1=CC=C(C=C1)C1=C(CN(C)C)C2=C(S1)N(CC1=C(F)C=CC=C1F)C(=O)N(C2=O)C1=CC=C(OC)N=N1

References

Synthesis Reference

Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T: Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2011 Jul 28;54(14):4998-5012. doi: 10.1021/jm200216q. Epub 2011 Jun 23.

General References
  1. Osuga Y, Seki Y, Tanimoto M, Kusumoto T, Kudou K, Terakawa N: Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: a randomized, double-blind, placebo-controlled study. Fertil Steril. 2020 Sep 7. pii: S0015-0282(20)30716-0. doi: 10.1016/j.fertnstert.2020.07.055. [Article]
  2. Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T: Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl )-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2011 Jul 28;54(14):4998-5012. doi: 10.1021/jm200216q. Epub 2011 Jun 23. [Article]
  3. Barra F, Seca M, Della Corte L, Giampaolino P, Ferrero S: Relugolix for the treatment of uterine fibroids. Drugs Today (Barc). 2019 Aug;55(8):503-512. doi: 10.1358/dot.2019.55.8.3020179. [Article]
  4. MacLean DB, Shi H, Faessel HM, Saad F: Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males. J Clin Endocrinol Metab. 2015 Dec;100(12):4579-87. doi: 10.1210/jc.2015-2770. Epub 2015 Oct 26. [Article]
  5. Michaud JE, Billups KL, Partin AW: Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther Adv Urol. 2015 Dec;7(6):378-87. doi: 10.1177/1756287215597633. [Article]
  6. Markham A: Relugolix: First Global Approval. Drugs. 2019 Apr;79(6):675-679. doi: 10.1007/s40265-019-01105-0. [Article]
  7. Kittai AS, Blank J, Graff JN: Gonadotropin-Releasing Hormone Antagonists in Prostate Cancer. Oncology (Williston Park). 2018 Dec 17;32(12):599-602, 604-6. [Article]
  8. Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B: Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. doi: 10.1056/NEJMoa2004325. Epub 2020 May 29. [Article]
  9. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]
  10. FDA News Release: FDA Approves First Oral Hormone Therapy for Treating Advanced Prostate Cancer [Link]
  11. GeekyMedics: How the Gonadal Axis Works [Link]
  12. FDA Approved Drug Products: MYFEMBREE (relugolix, estradiol, and norethindrone acetate) tablets, for oral use [Link]
PubChem Compound
10348973
PubChem Substance
347828195
ChemSpider
8524431
BindingDB
50347982
RxNav
2472778
ChEMBL
CHEMBL1800159
ZINC
ZINC000043206033
Wikipedia
Relugolix

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentEndometriosis1
3Active Not RecruitingTreatmentProstate Cancer1
3Active Not RecruitingTreatmentUterine Fibroids (Leiomyomas)1
3CompletedTreatmentEndometriosis1
3CompletedTreatmentEndometriosis related pain2
3CompletedTreatmentHeavy Menstrual Bleeding / Uterine Fibroids (Leiomyomas)3
3CompletedTreatmentUterine Fibroids (Leiomyomas)2
3SuspendedTreatmentContraception1
2CompletedTreatmentEndometriosis2
2CompletedTreatmentProstate Cancer2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral
Tablet, film coatedOral120 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8735401No2004-02-042024-02-04US flag
US10449191No2017-09-292037-09-29US flag
US10786501No2017-09-292037-09-29US flag
US10350170No2016-02-252036-02-25US flag
US8058280No2004-01-282024-01-28US flag
US7300935No2004-01-282024-01-28US flag
US9346822No2004-02-172024-02-17US flag
US11033551No2017-09-292037-09-29US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00198 mg/mLALOGPS
logP3.16ALOGPS
logP3.94ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)9.07ChemAxon
pKa (Strongest Basic)7.69ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area129.23 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity160.92 m3·mol-1ChemAxon
Polarizability62.44 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Peptide binding
Specific Function
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone...
Gene Name
GNRHR
Uniprot ID
P30968
Uniprot Name
Gonadotropin-releasing hormone receptor
Molecular Weight
37730.355 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]

Enzymes

Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Orgovyx (relugolix) tablets for oral use [Link]

Drug created on October 20, 2016 20:54 / Updated on June 26, 2021 13:10