Vismodegib

Identification

Summary

Vismodegib is a hedgehog pathway inhibitor used to treat patients with locally advanced or metastatic basal cell carcinoma.

Brand Names
Erivedge
Generic Name
Vismodegib
DrugBank Accession Number
DB08828
Background

Vismodegib inhibits the hedgehog signalling pathway and is indicated for treatment of adult basal cell carcinoma. FDA approved on Jan 30, 2012.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 421.297
Monoisotopic: 420.010218428
Chemical Formula
C19H14Cl2N2O3S
Synonyms
  • Vismodegib
  • Vismodégib
  • Vismodegibum
External IDs
  • GDC-0449
  • RG-3616

Pharmacology

Indication

Vismodegib is used for treating locally advanced or metastatic basal cell carcinoma in patients whose carcinoma has recurred after surgery, and in patients who are not candidates for surgery or radiation.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Vismodegib selectively binds to and inhibits the transmembrane protein Smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.

Mechanism of action

Mutations of the Hedgehog pathway may results in uncontrolled proliferation of skin basal cells. Vismodegib binds to and inhibits the transmembrane protein Smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.

TargetActionsOrganism
ASmoothened homolog
antagonist
Humans
Absorption

The absolute bioavailability of a single dose is 31.8%. Absorption is saturable and is not affected by food.

Volume of distribution

Vismodegib has a volume of distribution of 16.4 to 26.6 L.

Protein binding

Vismodegib is highly protein bound with plasma protein binding at about 99%. Vismodegib binds to the plasma proteins, albumin and alpha-1-acid glycoprotein (saturable bnding).

Metabolism

The main metabolic enzymes are CYP2C9 and CYP3A4, however more than 98% of total systemic vismodegib is not metabolized. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.

Route of elimination

Vismodegib is mostly excreted unchanged, and the main route of elimination is by the feces (82%) and the urine accounts for 4.4%.

Half-life

The half-life after a single dose is 12 days, and after continuous daily dosing is 4 days.

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Increased risk of embryo-fetal death and significant birth defects. Common adverse event include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.

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 Vismodegib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Vismodegib can be increased when combined with Abatacept.
AbemaciclibVismodegib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AbirateroneThe metabolism of Vismodegib can be decreased when combined with Abiraterone.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Vismodegib.
AcetohexamideThe metabolism of Vismodegib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Vismodegib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe metabolism of Vismodegib can be decreased when combined with Acetylsalicylic acid.
AdalimumabThe metabolism of Vismodegib can be increased when combined with Adalimumab.
AfatinibVismodegib may decrease the excretion rate of Afatinib which could result in a higher serum level.
Interactions
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Food Interactions
  • Take with or without food. Food does not affect absorption.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ErivedgeCapsule150 mgOralHoffmann La Roche2013-08-09Not applicableCanada flag
ErivedgeCapsule150 mg/1OralGenentech, Inc.2012-01-30Not applicableUS flag
ErivedgeCapsule150 mgOralRoche Registration Gmb H2020-12-22Not applicableEU flag

Categories

ATC Codes
L01XX43 — Vismodegib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Anilides
Direct Parent
Benzanilides
Alternative Parents
Phenylpyridines / 2-halobenzoic acids and derivatives / Benzamides / Benzenesulfonyl compounds / Benzoyl derivatives / Chlorobenzenes / Aryl chlorides / Vinylogous halides / Sulfones / Heteroaromatic compounds
show 8 more
Substituents
2-halobenzoic acid or derivatives / 2-phenylpyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzamide / Benzanilide / Benzenesulfonyl group / Benzoic acid or derivatives
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
sulfone, benzamides, pyridines, monochlorobenzenes (CHEBI:66903)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
25X868M3DS
CAS number
879085-55-9
InChI Key
BPQMGSKTAYIVFO-UHFFFAOYSA-N
InChI
InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)
IUPAC Name
2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-methanesulfonylbenzamide
SMILES
CS(=O)(=O)C1=CC(Cl)=C(C=C1)C(=O)NC1=CC=C(Cl)C(=C1)C1=CC=CC=N1

References

General References
  1. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2. [Article]
  2. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [Article]
KEGG Drug
D09992
PubChem Compound
24776445
PubChem Substance
175427109
ChemSpider
23337846
BindingDB
50249522
RxNav
1242987
ChEBI
66903
ChEMBL
CHEMBL473417
ZINC
ZINC000040899447
PharmGKB
PA166048558
PDBe Ligand
VIS
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vismodegib
PDB Entries
5l7i
FDA label
Download (211 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentCarcinoma, Basal Cell (BCC)1
4RecruitingTreatmentLocally advanced basal cell carcinoma (BCC) / Metastatic basal cell carcinoma (BCC)1
2Active Not RecruitingTreatmentBiliary Cancers / Bladder Cancer, Cancer / Neoplasms / Salivary Cancer / Tumors, Solid1
2Active Not RecruitingTreatmentCarcinoma, Basal Cell (BCC)2
2Active Not RecruitingTreatmentChondrosarcoma, Mesenchymal / Clear Cell Chondrosarcoma / Dedifferentiated Chondrosarcoma / Locally Advanced Chondrosarcoma / Metastatic Chondrosarcoma / Primary Central Chondrosarcoma / Unresectable Primary Central Chondrosarcoma1
2CompletedTreatmentAdenocarcinoma of the Stomach / Adenocarcinomas of the Gastroesophageal Junction / Advanced Gastric Cancer / Recurrent Gastric Cancer / Stage IIIA Gastric Cancer / Stage IIIB Gastric Cancer / Stage IIIC Gastric Cancer1
2CompletedTreatmentAdult Giant Cell Glioblastoma / Glioblastoma, Adult / Gliosarcoma, Adult / Recurrent Brain Tumor, Adult1
2CompletedTreatmentAdult Medulloblastoma1
2CompletedTreatmentBasal Cell Nevus Syndrome / Gorlin's Syndrome2
2CompletedTreatmentCancer of the Skin / Cutaneous Malignancy / Locally advanced basal cell carcinoma (BCC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral150 mg/1
CapsuleOral
Capsule, coatedOral150 mg
CapsuleOral150 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9278961No2016-03-082028-12-15US flag
US7888364No2011-02-152028-11-11US flag
US9790183No2005-09-022025-09-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility0.1 μg/mL and is pH dependent FDA label
logP2.7 FDA label
pKa3.8FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00173 mg/mLALOGPS
logP4.22ALOGPS
logP3.93ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)10.27ChemAxon
pKa (Strongest Basic)3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area76.13 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity107.81 m3·mol-1ChemAxon
Polarizability39.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9547
Blood Brain Barrier+0.9387
Caco-2 permeable+0.6048
P-glycoprotein substrateNon-substrate0.8443
P-glycoprotein inhibitor INon-inhibitor0.8663
P-glycoprotein inhibitor IINon-inhibitor0.9558
Renal organic cation transporterNon-inhibitor0.8925
CYP450 2C9 substrateNon-substrate0.6009
CYP450 2D6 substrateNon-substrate0.63
CYP450 3A4 substrateNon-substrate0.5083
CYP450 1A2 substrateNon-inhibitor0.6067
CYP450 2C9 inhibitorInhibitor0.9078
CYP450 2D6 inhibitorNon-inhibitor0.6638
CYP450 2C19 inhibitorInhibitor0.8515
CYP450 3A4 inhibitorInhibitor0.8452
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9282
Ames testNon AMES toxic0.8271
CarcinogenicityNon-carcinogens0.6746
BiodegradationNot ready biodegradable0.9956
Rat acute toxicity2.0840 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9973
hERG inhibition (predictor II)Non-inhibitor0.8224
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/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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0212900000-190a5fdca2d781122e92

Targets

Drugtargets2
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Details
1. Smoothened homolog
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Wnt-protein binding
Specific Function
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought t...
Gene Name
SMO
Uniprot ID
Q99835
Uniprot Name
Smoothened homolog
Molecular Weight
86395.95 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
Shown to be an inhibitor in vitro.
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [Article]
  2. Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]
  3. Vismodegib FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
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...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Shown to be an inhibitor in vitro.
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. Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Shown to be an inhibitor in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]
  2. Vismodegib [File]

Carriers

Details
1. Serum albumin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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

Transporters

Kind
Protein
Organism
Humans
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
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [Article]
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

Drug created on January 04, 2013 21:48 / Updated on September 19, 2021 19:53