Identification

Name
Elagolix
Accession Number
DB11979  (DB05694)
Type
Small Molecule
Groups
Approved, Investigational
Description

Elagolix has been used in trials studying the basic science and treatment of Endometriosis, Folliculogenesis, Uterine Fibroids, Heavy Uterine Bleeding, and Heavy Menstrual Bleeding. As of 24 July 2018, however, the U.S. Food and Drug Administration (FDA) approved AbbVie's elagolix under the brand name Orilissa as the first and only oral gonadotropin-releasing hormone (GnRH) antagonist specifically developed for women with moderate to severe endometriosis pain [7].

It has been determined that endometriosis is one of the most common gynecologic disorders in the United States [4, 5, 6]. In particular, estimates suggest that one in ten women of reproductive age is affected by endometriosis and experience debilitating pain symptoms [4, 5, 6]. Moreover, women who are affected by this condition can suffer for up to six to ten years and visit multiple physicians before receiving a proper diagnosis [4, 5, 6]. Subsequently, as Orilissa (elagolix) was approved by the FDA under priority review [7], this expedited new approval gives healthcare professionals another valuable option for treating the potentially unmet needs of women who are affected by endometriosis, depending on their specific type and severity of endometriosis pain.

Structure
Thumb
Synonyms
Not Available
External IDs
ABT-620 / NBI-56418
Product Ingredients
IngredientUNIICASInChI Key
Elagolix sodium5948VUI423832720-36-2DQYGXRQUFSRDCH-UQIIZPHYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OrilissaTablet, film coated150 mg/1OralAbbVie Inc.2018-07-23Not applicableUs
OrilissaTablet, film coated200 mg/1OralAbbVie Inc.2018-07-23Not applicableUs
Categories
UNII
5B2546MB5Z
CAS number
834153-87-6
Weight
Average: 631.6
Monoisotopic: 631.210561893
Chemical Formula
C32H30F5N3O5
InChI Key
HEAUOKZIVMZVQL-VWLOTQADSA-N
InChI
InChI=1S/C32H30F5N3O5/c1-19-28(21-11-6-14-26(45-2)29(21)34)30(43)40(18-25(20-9-4-3-5-10-20)38-16-8-15-27(41)42)31(44)39(19)17-22-23(32(35,36)37)12-7-13-24(22)33/h3-7,9-14,25,38H,8,15-18H2,1-2H3,(H,41,42)/t25-/m0/s1
IUPAC Name
4-{[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl]-1-phenylethyl]amino}butanoic acid
SMILES
COC1=C(F)C(=CC=C1)C1=C(C)N(CC2=C(C=CC=C2F)C(F)(F)F)C(=O)N(C[C@H](NCCCC(O)=O)C2=CC=CC=C2)C1=O

Pharmacology

Indication

Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis [Label].

Associated Conditions
Pharmacodynamics

During a three menstrual cycle study in healthy women, an elagolix 150 mg once daily regimen and a 200 mg twice daily regimen resulted in an ovulation rate of about 50% and 32%, respectively [Label]. In Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for the 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen [Label].

Furthermore, the effect of elagolix on the QTc interval was investigated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women [Label]. Elagolix concentrations in subjects administered a single dose of 1200 mg was seventeen times higher than the concentration in subjects given elagolix 200 mg twice daily. Nevertheless, there was no clinically relevant prolongation of the QTc interval [Label].

Mechanism of action

Endometriosis develops when tissue that is similar to the kind that is normally located in the uterus starts to grow outside of the uterus [4, 6]. Such growth leads to various symptoms like pain during periods, pelvic pain between periods, and pain during sexual intercourse [4, 6]. The growths themselves are referred to as lesions and frequently develop on the ovaries, fallopian tubes, and other areas around the uterus, including the bowel or bladder [4, 6]. The growth of these lesions is dependent upon the estrogen hormone [4].

Elagolix is an orally-administered, nonpeptide small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland [Label]. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

TargetActionsOrganism
UGonadotropin-releasing hormone receptorNot AvailableHuman
Absorption

The Tmax of elagolix is reported as being 1.0 hours [Label]. The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively [Label].

Volume of distribution

The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen [Label].

Protein binding

The percentage bound to human plasma proteins for elagolix has been documented as 80% [Label].

Metabolism

Elagolix is predominantly metabolized by the CYP3A family of isoenzymes despite participating in minor metabolic pathways with the CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) enzymes as well [Label]. The primary metabolite of elagolix, referred to as NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino}-butyrate) [2], is not believed to possess any significant biologic activity due to its low plasma exposure and an observed potency that is exceptionally less than the parent elagolix compound (Ki value of 3.5 compared to 0.9 nM) [1].

Route of elimination

The primary route of elimination of elagolix is via hepatic metabolism [Label].

Half life

The terminal phase elimination half-life of elagolix is recorded as being 4 to 6 hours [Label].

Clearance

The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen [Label].

Toxicity

In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed [Label]. Common adverse reactions of elagolix include hot flush, headache, nausea, insomnia, mood alterations, amenorrhea, depression, anxiety, arthralgia, bone loss, changes in menstrual bleeding patterns, suicidal ideation and behavior, exacerbation of existing mood disorders, and/or hepatic transaminase elevations [Label].

The recommended duration of use for elagolix is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD) [Label]. BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [Label]. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Elagolix can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Elagolix.
4-MethoxyamphetamineThe metabolism of Elagolix can be decreased when combined with 4-Methoxyamphetamine.
AbemaciclibThe serum concentration of Elagolix can be increased when it is combined with Abemaciclib.
AbirateroneThe metabolism of Elagolix can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Elagolix can be decreased when combined with Acebutolol.
AcetaminophenThe serum concentration of Elagolix can be increased when it is combined with Acetaminophen.
AcetylcysteineThe excretion of Elagolix can be decreased when combined with Acetylcysteine.
Acetylsalicylic acidThe metabolism of Elagolix can be decreased when combined with Acetylsalicylic acid.
AdenineThe metabolism of Elagolix can be decreased when combined with Adenine.
Food Interactions
Not Available

References

General References
  1. Ezzati M, Carr BR: Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain. Womens Health (Lond). 2015 Jan;11(1):19-28. doi: 10.2217/whe.14.68. [PubMed:25581052]
  2. Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP: Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab. 2009 Feb;94(2):545-51. doi: 10.1210/jc.2008-1695. Epub 2008 Nov 25. [PubMed:19033369]
  3. Melis GB, Neri M, Corda V, Malune ME, Piras B, Pirarba S, Guerriero S, Orru M, D'Alterio MN, Angioni S, Paoletti AM: Overview of elagolix for the treatment of endometriosis. Expert Opin Drug Metab Toxicol. 2016 May;12(5):581-8. doi: 10.1517/17425255.2016.1171316. [PubMed:27021205]
  4. Giudice LC: Clinical practice. Endometriosis. N Engl J Med. 2010 Jun 24;362(25):2389-98. doi: 10.1056/NEJMcp1000274. [PubMed:20573927]
  5. Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT: Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011 Aug;96(2):366-373.e8. doi: 10.1016/j.fertnstert.2011.05.090. Epub 2011 Jun 30. [PubMed:21718982]
  6. U.S. Department of Health and Human Services (2002): Endometriosis [File]
  7. AbbVie Orilissa (elagolix) FDA Approval Press Release [File]
External Links
PubChem Compound
11250647
PubChem Substance
347828301
ChemSpider
9425680
ChEMBL
CHEMBL1208155
Wikipedia
Elagolix
FDA label
Download (631 KB)
MSDS
Download (174 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceFolliculogenesis1
2CompletedTreatmentEndometriosis3
2CompletedTreatmentEndometriosis, Pain1
2CompletedTreatmentEndometriosis / Endometriosis, Pain / Pain NOS1
2CompletedTreatmentHeavy Uterine Bleeding / Uterine Leiomyomas2
3Active Not RecruitingTreatmentHeavy Menstrual Bleeding / Uterine Leiomyomas3
3CompletedTreatmentEndometriosis4
3RecruitingTreatmentEndometriosis1
3RecruitingTreatmentHeavy Menstrual Bleeding / Uterine Leiomyomas1
3TerminatedTreatmentEndometriosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral150 mg/1
Tablet, film coatedOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7419983No2008-09-022024-07-06Us
US7462625No2008-12-092021-01-25Us
US7176211No2007-02-132024-07-06Us
US7179815No2007-02-202021-03-07Us
US7056927No2006-06-062024-09-10Us
US6872728No2005-03-292021-01-25Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1 mg/mLMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.00243 mg/mLALOGPS
logP4.68ALOGPS
logP3.14ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)3.86ChemAxon
pKa (Strongest Basic)9.04ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.18 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity156.06 m3·mol-1ChemAxon
Polarizability59.57 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
Trifluoromethylbenzenes / Anisoles / Methoxybenzenes / Phenoxy compounds / Aralkylamines / Alkyl aryl ethers / Amino fatty acids / Fluorobenzenes / Pyrimidones / Hydropyrimidines
show 16 more
Substituents
Gamma amino acid or derivatives / Trifluoromethylbenzene / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene / Alkyl aryl ether / Amino fatty acid / Halobenzene / Pyrimidone
show 35 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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

Enzymes

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Substrate
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:
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da

Drug created on October 20, 2016 15:07 / Updated on November 02, 2018 09:02