Fulvestrant

Identification

Summary

Fulvestrant is an estrogen receptor antagonist used to treat HR+ breast cancer that may also be HER2-.

Brand Names
Faslodex
Generic Name
Fulvestrant
DrugBank Accession Number
DB00947
Background

Fulvestrant is a drug treatment of hormone receptor (HR)-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor. While it is used as monotherapy for the treatment of breast cancers, it is also used in combination with alpelisib for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 606.78
Monoisotopic: 606.316607362
Chemical Formula
C32H47F5O3S
Synonyms
  • (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1(10),2,4-triene-3,17-diol
  • Fulvestrant
External IDs
  • ICI 182,780
  • ICI 182780
  • ICI-182780
  • ZD-9238
  • ZD9238

Pharmacology

Indication

For the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy, as monotherapy or in combination with other antineoplastic agents.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Fulvestrant for intramuscular administration is an estrogen receptor antagonist without known agonist effects.

Mechanism of action

Fulvestrant competitively and reversibly binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, fulvestrant binds to the receptors and downregulates them so that estrogen is no longer able to bind to these receptors. Second, fulvestrant degrades the estrogen receptors to which it is bound. Both of these mechanisms inhibit the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines.

TargetActionsOrganism
AEstrogen receptor alpha
antagonist
Humans
Absorption

Not Available

Volume of distribution
  • 3 to 5 L/kg
Protein binding

99% (mainly VLDL, LDL, and HDL)

Metabolism

Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.

Route of elimination

Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%).

Half-life

40 days

Clearance

Not Available

Adverse Effects
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Toxicity

There is no clinical experience with overdosage in humans.

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
AdenineThe metabolism of Fulvestrant can be decreased when combined with Adenine.
AmitriptylineThe metabolism of Fulvestrant can be decreased when combined with Amitriptyline.
AtazanavirThe metabolism of Fulvestrant can be decreased when combined with Atazanavir.
CarbamazepineThe metabolism of Fulvestrant can be increased when combined with Carbamazepine.
DacomitinibThe metabolism of Fulvestrant can be decreased when combined with Dacomitinib.
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Fulvestrant.
DasabuvirThe metabolism of Fulvestrant can be decreased when combined with Dasabuvir.
DeferasiroxThe metabolism of Fulvestrant can be decreased when combined with Deferasirox.
DesogestrelThe metabolism of Fulvestrant can be increased when combined with Desogestrel.
EfavirenzThe metabolism of Fulvestrant can be increased when combined with Efavirenz.
Interactions
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act FulvestrantSolution50 mg / mLIntramuscularActavis Pharma CompanyNot applicableNot applicableCanada flag
FaslodexInjection, solution250 mg/5mlIntramuscularAstra Zeneca Ab2016-09-20Not applicableEU flag
FaslodexSolution50 mg / mLIntramuscularAstra Zeneca2004-06-14Not applicableCanada flag
FaslodexInjection, solution250 mg/5mlIntramuscularAstra Zeneca Ab2016-09-20Not applicableEU flag
FaslodexInjection50 mg/1mLIntramuscularAstraZeneca Pharmaceuticals LP2010-11-01Not applicableUS flag
FulvestrantInjection250 mg/5mLIntramuscularActavis Pharma, Inc.2019-08-22Not applicableUS flag
FulvestrantInjection, solution50 mg/1mLIntramuscularFresenius Kabi USA, LLC2019-05-20Not applicableUS flag
Fulvestrant InjectionSolution50 mg / mLIntramuscularSandoz Canada Incorporated2019-02-01Not applicableCanada flag
Fulvestrant InjectionSolution50 mg / mLIntramuscularAccord Healthcare IncNot applicableNot applicableCanada flag
Fulvestrant InjectionSolution50 mg / mLIntramuscularMylan Pharmaceuticals2020-04-27Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-fulvestrantSolution50 mg / mLIntramuscularApotex CorporationNot applicableNot applicableCanada flag
FulvestrantInjection50 mg/1mLIntramuscularNorthstar RxLLC2019-05-292022-05-22US flag
FulvestrantInjection50 mg/1mLIntramuscularGlenmark Pharmaceuticals Inc., USA2019-08-22Not applicableUS flag
FulvestrantInjection50 mg/1mLIntramuscularChia Tai Tianqing Pharmaceutical Group Co., Ltd.2021-04-01Not applicableUS flag
FulvestrantInjection, solution50 mg/1mLIntramuscularDr.Reddy's Laboratories Inc2020-08-17Not applicableUS flag
FulvestrantInjection50 mg/1mLIntramuscularMylan Institutional LLC2019-09-09Not applicableUS flag
FulvestrantInjection, solution250 mg/5mLIntramuscularAmneal Pharmaceuticals LLC2019-03-04Not applicableUS flag
FulvestrantInjection50 mg/1mLIntramuscularSandoz Inc2019-05-29Not applicableUS flag
FulvestrantInjection50 mg/1mLIntramuscularHBT Labs, Inc.2019-11-21Not applicableUS flag
FulvestrantInjection, solution50 mg/1mLIntramuscularBluePoint Laboratories2019-08-01Not applicableUS flag

Categories

ATC Codes
L02BA03 — Fulvestrant
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrogens and derivatives
Alternative Parents
3-hydroxysteroids / 17-hydroxysteroids / Phenanthrenes and derivatives / Tetralins / 1-hydroxy-2-unsubstituted benzenoids / Sulfoxides / Secondary alcohols / Cyclic alcohols and derivatives / Sulfinyl compounds / Organofluorides
show 3 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / 17-hydroxysteroid / 3-hydroxysteroid / Alcohol / Alkyl fluoride / Alkyl halide / Aromatic homopolycyclic compound / Benzenoid / Cyclic alcohol / Estrogen-skeleton
show 13 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
22X328QOC4
CAS number
129453-61-8
InChI Key
VWUXBMIQPBEWFH-WCCTWKNTSA-N
InChI
InChI=1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,41?/m1/s1
IUPAC Name
(1S,3aS,3bR,4R,9bS,11aS)-11a-methyl-4-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]-1H,2H,3H,3aH,3bH,4H,5H,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,7-diol
SMILES
[H][C@@]12CC[C@H](O)[C@@]1(C)CC[C@]1([H])C3=CC=C(O)C=C3C[C@@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)[C@@]21[H]

References

General References
  1. Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N: Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol. 2005 Jul 15;239(1-2):27-36. [Article]
  2. Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. doi: 10.1517/14656561003641982. [Article]
  3. Bross PF, Cohen MH, Williams GA, Pazdur R: FDA drug approval summaries: fulvestrant. Oncologist. 2002;7(6):477-80. [Article]
Human Metabolome Database
HMDB0015082
KEGG Drug
D01161
PubChem Compound
17756771
PubChem Substance
46508664
ChemSpider
94553
BindingDB
50238741
RxNav
282357
ChEBI
31638
ChEMBL
CHEMBL1358
Therapeutic Targets Database
DAP000319
PharmGKB
PA164747170
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fulvestrant
FDA label
Download (520 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentNeoplasms, Breast1
4CompletedOtherLocally Advanced or / Metastatic Breast Cancer1
4Not Yet RecruitingTreatmentMetastatic Breast Cancer1
4RecruitingTreatmentMetastatic Breast Cancer1
4RecruitingTreatmentNeoplasms, Breast / Neoplasms, Metastasis1
4TerminatedTreatmentMetastatic Breast Cancer1
3Active Not RecruitingTreatmentAdvanced Breast Cancer2
3Active Not RecruitingTreatmentBreast Cancer6
3Active Not RecruitingTreatmentBreast Cancer Stage IIIc / Breast Cancer, Stage II / Breast Cancer, Stage IIIB / Estrogen Receptor Positive Breast Cancer / HER 2 Negative Breast Cancer / Invasive Ductal Carcinoma, Breast / Invasive Lobular Breast Carcinoma / Recurrent Breast Cancer / Stage IIIA Breast Cancer1
3Active Not RecruitingTreatmentBreast Cancer / HER 2 Negative Breast Cancer / Hormone Receptor Positive Tumor1

Pharmacoeconomics

Manufacturers
  • Astrazeneca pharmaceuticals lp
Packagers
  • AstraZeneca Inc.
  • Vetter Pharma Fertigung GmbH and Co. KG
Dosage Forms
FormRouteStrength
InjectionIntramuscular
Injection, solutionIntramuscular; Parenteral
SolutionIntramuscular50 mg / mL
InjectionIntramuscular250 mg/5mL
InjectionIntramuscular50 mg/1mL
Injection, solutionIntramuscular250 mg/5mL
Injection, solutionIntramuscular50 mg/1mL
SolutionIntramuscular250 mg
Injection, solutionParenteral
Injection, solutionIntramuscular
Injection, solutionIntramuscular250 mg
Injection, solution
SolutionIntramuscular250 mg/5ml
Injection, solution250 mg/5ml
Prices
Unit descriptionCostUnit
Faslodex 125 mg/2.5 ml syringe240.83USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2351004No2003-02-182021-01-08Canada flag
US6774122Yes2004-08-102021-07-09US flag
US7456160Yes2008-11-252021-07-09US flag
US8329680Yes2012-12-112021-07-09US flag
US8466139Yes2013-06-182021-07-09US flag
US10188663No2019-01-292034-02-14US flag
US9271990No2016-03-012034-05-17US flag
US9833459No2017-12-052034-02-14US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP8.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00672 mg/mLALOGPS
logP6.54ALOGPS
logP7.57ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)10.32ChemAxon
pKa (Strongest Basic)-0.88ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity155.34 m3·mol-1ChemAxon
Polarizability65.88 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9217
Caco-2 permeable-0.5095
P-glycoprotein substrateSubstrate0.722
P-glycoprotein inhibitor INon-inhibitor0.6251
P-glycoprotein inhibitor IINon-inhibitor0.967
Renal organic cation transporterNon-inhibitor0.7568
CYP450 2C9 substrateNon-substrate0.7667
CYP450 2D6 substrateNon-substrate0.7737
CYP450 3A4 substrateSubstrate0.6945
CYP450 1A2 substrateNon-inhibitor0.6842
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.658
CYP450 3A4 inhibitorInhibitor0.7959
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6701
Ames testNon AMES toxic0.6318
CarcinogenicityNon-carcinogens0.75
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6310 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6158
hERG inhibition (predictor II)Inhibitor0.7955
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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Details
1. Estrogen receptor alpha
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Curran M, Wiseman L: Fulvestrant. Drugs. 2001;61(6):807-13; discussion 814. [Article]
  2. Elkak AE, Mokbel K: Pure antiestrogens and breast cancer. Curr Med Res Opin. 2001;17(4):282-9. [Article]
  3. Dow KH: Existing and emerging endocrine therapies for breast cancer. Cancer Nurs. 2002 Apr;25 Suppl 2:6S-11S. [Article]
  4. Bundred N, Howell A: Fulvestrant (Faslodex): current status in the therapy of breast cancer. Expert Rev Anticancer Ther. 2002 Apr;2(2):151-60. [Article]
  5. Morris C, Wakeling A: Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer. 2002 Dec;9(4):267-76. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Kabos P, Borges VF: Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer. Expert Opin Pharmacother. 2010 Apr;11(5):807-16. doi: 10.1517/14656561003641982. [Article]
  8. McKeage K, Curran MP, Plosker GL: Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Drugs. 2004;64(6):633-48. [Article]
  9. Jones SE, Pippen J: Effectiveness and tolerability of fulvestrant in postmenopausal women with hormone receptor-positive breast cancer. Clin Breast Cancer. 2005 Apr;6 Suppl 1:S9-14. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
The FDA label for Fluvesrant indicates that this enzyme action is unlikely to be involved in any drug interactions. No dose adjustments are recommended.
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...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Robertson JF, Harrison M: Fulvestrant: pharmacokinetics and pharmacology. Br J Cancer. 2004 Mar;90 Suppl 1:S7-10. doi: 10.1038/sj.bjc.6601630. [Article]
  2. Rocca A, Maltoni R, Bravaccini S, Donati C, Andreis D: Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence. Cancer Manag Res. 2018 Aug 30;10:3083-3099. doi: 10.2147/CMAR.S137772. eCollection 2018. [Article]
  3. Fluvestrant FDA label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Dancygier H. (2010). Clinical Hepatology. Springer-Verlag. [ISBN:978-3-642-04509-7]

Drug created on June 13, 2005 13:24 / Updated on July 29, 2021 06:27