Vismodegib

Identification

Name

Vismodegib

Accession Number

DB08828

Description

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Vismodegib (DB08828)

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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.

Associated Conditions

• Locally Advanced Basal Cell Carcinoma
• Metastatic Basal cell carcinoma

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

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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.

Target	Actions	Organism
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

Learn about our commercial Adverse Effects data.

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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.

Affected organisms

• Humans and other mammals

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Vismodegib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Vismodegib can be increased when combined with Abatacept.
Abemaciclib	Vismodegib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Abiraterone	The metabolism of Vismodegib can be decreased when combined with Abiraterone.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Vismodegib.
Acetohexamide	The metabolism of Acetohexamide can be decreased when combined with Vismodegib.
Acetyl sulfisoxazole	The metabolism of Vismodegib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be decreased when combined with Vismodegib.
Adalimumab	The metabolism of Vismodegib can be increased when combined with Adalimumab.
Afatinib	Vismodegib may decrease the excretion rate of Afatinib which could result in a higher serum level.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Take with or without food. Food does not affect absorption.

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Erivedge	Capsule		Oral	Hoffmann La Roche	2013-08-09	Not applicable
Erivedge	Capsule	150 mg/1	Oral	Genentech, Inc.	2012-01-30	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

ATC Codes

L01XX43 — Vismodegib

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amides
• Amines
• Aniline Compounds
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Hedgehog Pathway Inhibitor
• P-glycoprotein substrates
• Smoothened Receptor Antagonists

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 / Secondary carboxylic acid amides / Azacyclic compounds / Hydrocarbon derivatives / Organic oxides / Organochlorides / Organonitrogen compounds / Organooxygen compounds / Organopnictogen compounds

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Substituents

2-halobenzoic acid or derivatives / 2-phenylpyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzamide / Benzanilide / Benzenesulfonyl group / Benzoic acid or derivatives / Benzoyl / Carboxamide group / Carboxylic acid derivative / Chlorobenzene / Halobenzene / Halobenzoic acid or derivatives / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Organosulfur compound / Pyridine / Secondary carboxylic acid amide / Sulfone / Sulfonyl / Vinylogous halide

show 23 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

sulfone, benzamides, pyridines, monochlorobenzenes (CHEBI:66903)

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. [PubMed:19726763]
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. [PubMed:23662017]

External Links

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

AHFS Codes

• 10:00.00 — Antineoplastic Agents

PDB Entries

5l7i

FDA label

Download (211 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Basal Cell Carcinoma (BCC)	1
4	Recruiting	Treatment	Locally Advanced Basal Cell Carcinoma / Metastatic Basal cell carcinoma	1
2	Active Not Recruiting	Treatment	Basal Cell Carcinoma (BCC)	2
2	Active Not Recruiting	Treatment	Biliary Cancer / Cancer, Bladder / Neoplasms / Salivary Cancer / Tumors, Solid	1
2	Active Not Recruiting	Treatment	Chondrosarcoma, Mesenchymal / Clear Cell Chondrosarcoma / Dedifferentiated Chondrosarcoma / Locally Advanced Chondrosarcoma / Metastatic Chondrosarcoma / Primary Central Chondrosarcoma / Unresectable Primary Central Chondrosarcoma	1
2	Active Not Recruiting	Treatment	Stomach Neoplasms	1
2	Completed	Treatment	Adenocarcinoma 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 Cancer	1
2	Completed	Treatment	Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Recurrent Adult Brain Tumor	1
2	Completed	Treatment	Adult Medulloblastoma	1
2	Completed	Treatment	Basal Cell Carcinoma (BCC)	6

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule	Oral	150 MG
Capsule	Oral	150 mg/1
Capsule		150 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
US9278961	No	2016-03-08	2028-12-15
US7888364	No	2011-02-15	2028-11-11

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	0.1 μg/mL and is pH dependent	FDA label
logP	2.7	FDA label
pKa	3.8	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.00173 mg/mL	ALOGPS
logP	4.22	ALOGPS
logP	3.93	ChemAxon
logS	-5.4	ALOGPS
pKa (Strongest Acidic)	10.27	ChemAxon
pKa (Strongest Basic)	3.7	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	76.13 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	107.81 m3·mol-1	ChemAxon
Polarizability	39.49 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9547
Blood Brain Barrier	+	0.9387
Caco-2 permeable	+	0.6048
P-glycoprotein substrate	Non-substrate	0.8443
P-glycoprotein inhibitor I	Non-inhibitor	0.8663
P-glycoprotein inhibitor II	Non-inhibitor	0.9558
Renal organic cation transporter	Non-inhibitor	0.8925
CYP450 2C9 substrate	Non-substrate	0.6009
CYP450 2D6 substrate	Non-substrate	0.63
CYP450 3A4 substrate	Non-substrate	0.5083
CYP450 1A2 substrate	Non-inhibitor	0.6067
CYP450 2C9 inhibitor	Inhibitor	0.9078
CYP450 2D6 inhibitor	Non-inhibitor	0.6638
CYP450 2C19 inhibitor	Inhibitor	0.8515
CYP450 3A4 inhibitor	Inhibitor	0.8452
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.9282
Ames test	Non AMES toxic	0.8271
Carcinogenicity	Non-carcinogens	0.6746
Biodegradation	Not ready biodegradable	0.9956
Rat acute toxicity	2.0840 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9973
hERG inhibition (predictor II)	Non-inhibitor	0.8224

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-00di-0212900000-190a5fdca2d781122e92

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Drug created on January 04, 2013 14:48 / Updated on October 27, 2020 11:13