Degarelix

Identification

Summary

Degarelix is a GnRH receptor antagonist used in the management of advanced prostate cancer.

Brand Names
Firmagon
Generic Name
Degarelix
DrugBank Accession Number
DB06699
Background

Degarelix is used for the treatment of advanced prostate cancer. Degarelix is a synthetic peptide derivative drug which binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocks interaction with GnRH. This antagonism reduces luteinising hormone (LH) and follicle-stimulating hormone (FSH) which ultimately causes testosterone suppression. Reduction in testosterone is important in treating men with advanced prostate cancer. Chemically, it is a synthetic linear decapeptide amide with seven unnatural amino acids, five of which are D-amino acids. FDA approved on December 24, 2008.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 1632.29
Monoisotopic: 1630.748797
Chemical Formula
C82H103ClN18O16
Synonyms
  • Degarelix
External IDs
  • FE200486

Pharmacology

Indication

In Canada and the US, degarelix is indicated for the treatment of advanced prostate cancer in patients requiring androgen deprivation therapy.3,4 In the EU, it is more specifically indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer, and for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer, in combination with radiotherapy or as a neo-adjuvant prior to radiotherapy.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAdvanced hormone dependent prostate cancer••••••••••••••••••••••••••• ••••••• ••• ••••••••
Used as adjunct in combination to treatAdvanced hormone dependent prostate cancer••••••••••••••••••••••••••• ••••••• ••• ••••••••
Treatment ofAdvanced hormone dependent prostate cancer•••••••••••••••••••••• ••••••• ••• ••••••••
Treatment ofAdvanced prostate cancer•••••••••••••••••••••• ••••••• ••• ••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Degarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes.

Mechanism of action

Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Humans
Absorption

Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days.

Volume of distribution

Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L

Protein binding

90% of the drug is bound to plasma proteins.

Metabolism

70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes.

Route of elimination

Fecal (70% to 80%) and renal (20%-30% of unchanged drug)

Half-life

Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days.

Clearance

Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.

Adverse Effects
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Toxicity

The most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT).

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
AcrivastineThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Acrivastine.
AdenosineThe risk or severity of QTc prolongation can be increased when Degarelix is combined with Adenosine.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Degarelix.
AlbuterolThe risk or severity of QTc prolongation can be increased when Salbutamol is combined with Degarelix.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Degarelix.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Degarelix acetate hydrateEXT215F4ZU934246-14-7AUTFSFUMNFDPLH-KYMMNHPFSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Degarelix AccordInjection, powder, for solution80 mgSubcutaneousAccord Healthcare S.L.U.2023-11-28Not applicableEU flag
Degarelix AccordInjection, powder, for solution80 mgSubcutaneousAccord Healthcare S.L.U.2023-11-28Not applicableEU flag
Degarelix AccordInjection, powder, for solution120 mgSubcutaneousAccord Healthcare S.L.U.2023-11-28Not applicableEU flag
FirmagonInjection, powder, for solution120 mgSubcutaneousFerring Pharmaceuticals2016-09-08Not applicableEU flag
FirmagonPowder, for solution80 mg / vialSubcutaneousFerring Pharmaceuticals2009-11-24Not applicableCanada flag

Categories

ATC Codes
L02BX02 — Degarelix
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Peptides / Phenylalanine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Serine and derivatives / Alpha amino acid amides / Alanine and derivatives / N-phenylureas / Naphthalenes
show 26 more
Substituents
1,3-diazinane / Acetamide / Alanine or derivatives / Alcohol / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid or derivatives / Amphetamine or derivatives
show 54 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
SX0XJI3A11
CAS number
214766-78-6
InChI Key
MEUCPCLKGZSHTA-XYAYPHGZSA-N
InChI
InChI=1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66+,67+,68+/m1/s1
IUPAC Name
(4S)-N-{4-[(2S)-2-{[(1R)-2-[4-(carbamoylamino)phenyl]-1-{[(1S)-1-{[(2S)-1-[(2S)-2-{[(1R)-1-carbamoylethyl]carbamoyl}pyrrolidin-1-yl]-1-oxo-6-[(propan-2-yl)amino]hexan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}ethyl]carbamoyl}-2-[(2S)-2-[(2R)-2-[(2R)-3-(4-chlorophenyl)-2-[(2R)-2-acetamido-3-(naphthalen-2-yl)propanamido]propanamido]-3-(pyridin-3-yl)propanamido]-3-hydroxypropanamido]ethyl]phenyl}-2,6-dioxo-1,3-diazinane-4-carboxamide
SMILES
CC(C)C[C@H](NC(=O)[C@@H](CC1=CC=C(NC(N)=O)C=C1)NC(=O)[C@H](CC1=CC=C(NC(=O)[C@@H]2CC(=O)NC(=O)N2)C=C1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC1=CC=CN=C1)NC(=O)[C@@H](CC1=CC=C(Cl)C=C1)NC(=O)[C@@H](CC1=CC=C2C=CC=CC2=C1)NC(C)=O)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O

References

Synthesis Reference

Carin WINDERSTROM, "KIT AND METHOD FOR PREPARATION OF A DEGARELIX SOLUTION." U.S. Patent US20100286603, issued November 11, 2010.

US20100286603
General References
  1. Steinberg M: Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther. 2009;31 Pt 2:2312-31. doi: 10.1016/j.clinthera.2009.11.009. [Article]
  2. Persson BE, Kold Olesen T, Jensen JK: Degarelix: a new approach for the treatment of prostate cancer. Neuroendocrinology. 2009;90(3):235-44. doi: 10.1159/000228832. Epub 2009 Jul 14. [Article]
  3. FDA Approved Drug Products: Firmagon (degarelix) powder for solution for subcutaneous injection (February 2020) [Link]
  4. Health Canada Approved Drug Products: Firmagon (degarelix) powder for solution for subcutaneous injection [Link]
  5. EMA Summary of Product Characteristics: Firmagon (degarelix) powder for solution for subcutaneous injection [Link]
KEGG Drug
D08901
PubChem Compound
16136245
PubChem Substance
99443253
ChemSpider
17292756
BindingDB
50102450
RxNav
475230
ChEBI
135961
ChEMBL
CHEMBL415606
PharmGKB
PA165958373
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Degarelix
FDA label
Download (448 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4Active Not RecruitingBasic ScienceAging / Hypoestrogenism / Menopause / Women1somestatusstop reasonjust information to hide
4CompletedOtherCardiovascular Disease (CVD) / Neoplasms of the Prostate1somestatusstop reasonjust information to hide
4CompletedTreatmentProstate Cancer1somestatusstop reasonjust information to hide
4Not Yet RecruitingBasic ScienceAdiposity / Aging / Hypoestrogenism / Menopause1somestatusstop reasonjust information to hide
4RecruitingBasic ScienceAging / Menopause / Obesity, Abdominal / Weight Gain1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionParenteral; Subcutaneous120 MG
Injection, powder, for solutionParenteral; Subcutaneous80 MG
Injection, powder, lyophilized, for solution; kitSubcutaneous20 mg/1mL
Injection, powder, lyophilized, for solution; kitSubcutaneous40 mg/1mL
Powder, for solutionSubcutaneous120 mg / vial
Powder, for solutionSubcutaneous80 mg / vial
Powder, meteredSubcutaneous20 mg/1mL
Powder, meteredSubcutaneous40 mg/1mL
Injection, powder, lyophilized, for solutionSubcutaneous120 mg
Injection, powder, lyophilized, for solutionSubcutaneous80 mg
PowderSubcutaneous
SolutionSubcutaneous88.200 mg
Injection, powder, for solutionSubcutaneous120 mg
Injection, powder, for solutionSubcutaneous80 mg
PowderSubcutaneous120 mg/1vial
PowderSubcutaneous80 mg/1vial
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2286190No2007-01-092018-04-13Canada flag
US5925730No1999-07-202021-05-18US flag
US9579359No2017-02-282029-02-10US flag
US9415085No2016-08-162032-04-27US flag
US10695398No2020-06-302032-04-27US flag
US10729739No2020-08-042029-02-10US flag
US10973870No2021-04-132029-02-10US flag
US11766468No2012-04-272032-04-27US flag
US11826397No2012-04-272032-04-27US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0041 mg/mLALOGPS
logP2.66ALOGPS
logP0.18Chemaxon
logS-5.6ALOGPS
pKa (Strongest Acidic)10.55Chemaxon
pKa (Strongest Basic)11.16Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count18Chemaxon
Hydrogen Donor Count17Chemaxon
Polar Surface Area512.87 Å2Chemaxon
Rotatable Bond Count41Chemaxon
Refractivity431.13 m3·mol-1Chemaxon
Polarizability168.98 Å3Chemaxon
Number of Rings8Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8352
Blood Brain Barrier-0.953
Caco-2 permeable-0.7556
P-glycoprotein substrateSubstrate0.8461
P-glycoprotein inhibitor INon-inhibitor0.6672
P-glycoprotein inhibitor IINon-inhibitor0.7791
Renal organic cation transporterNon-inhibitor0.8579
CYP450 2C9 substrateNon-substrate0.7299
CYP450 2D6 substrateNon-substrate0.8156
CYP450 3A4 substrateSubstrate0.6482
CYP450 1A2 substrateNon-inhibitor0.8566
CYP450 2C9 inhibitorNon-inhibitor0.6493
CYP450 2D6 inhibitorNon-inhibitor0.8566
CYP450 2C19 inhibitorNon-inhibitor0.7291
CYP450 3A4 inhibitorNon-inhibitor0.5961
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8478
Ames testNon AMES toxic0.652
CarcinogenicityNon-carcinogens0.7848
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7005 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8534
hERG inhibition (predictor II)Inhibitor0.5235
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-01pc-1311094000-f9acc076ac88d6a8faa9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03y0-1000169000-ac2fe33e15cdb7a73299
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-03k9-3531295001-e561449a9dd3a344593e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-02ta-1000293000-8596ba6a17dcd371fd48
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-7904162000-3fe2009f5af6feb556ee
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-02tc-7412293002-1dc6e39e17f55cc1c6b1
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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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. Steinberg M: Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther. 2009;31 Pt 2:2312-31. doi: 10.1016/j.clinthera.2009.11.009. [Article]
  2. Kirby RS, Fitzpatrick JM, Clarke N: Abarelix and other gonadotrophin-releasing hormone antagonists in prostate cancer. BJU Int. 2009 Dec;104(11):1580-4. doi: 10.1111/j.1464-410X.2009.08924.x. [Article]
  3. Anderson J: Degarelix: a novel gonadotropin-releasing hormone blocker for the treatment of prostate cancer. Future Oncol. 2009 May;5(4):433-43. doi: 10.2217/fon.09.24. [Article]
  4. Samant MP, Miller C, Hong DJ, Koerber SC, Croston G, Rivier CL, Rivier JE: Synthesis and biological activity of GnRH antagonists modified at position 3 with 3-(2-methoxy-5-pyridyl)-alanine. J Pept Res. 2005 Feb;65(2):284-91. [Article]

Drug created at May 06, 2010 16:15 / Updated at July 14, 2024 17:59