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

Similar Structures

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.

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Associated Conditions

Contraindications & Blackbox Warnings

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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

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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.

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 Vismodegib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazole	The metabolism of Vismodegib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acid	The metabolism of Vismodegib can be decreased when combined with Acetylsalicylic acid.
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.

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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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Erivedge	Capsule	150 mg	Oral	Hoffmann La Roche	2013-08-09	Not applicable
Erivedge	Capsule	150 mg/1	Oral	Genentech, Inc.	2012-01-30	Not applicable
Erivedge	Capsule	150 mg	Oral	Roche Registration Gmb H	2020-12-22	Not applicable

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

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]
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]

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

PDB Entries

5l7i

FDA label

Download (211 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Carcinoma, Basal Cell (BCC)	1
4	Recruiting	Treatment	Locally advanced basal cell carcinoma (BCC) / Metastatic basal cell carcinoma (BCC)	1
2	Active Not Recruiting	Treatment	Biliary Cancers / Bladder Cancer, Cancer / Neoplasms / Salivary Cancer / Tumors, Solid	1
2	Active Not Recruiting	Treatment	Carcinoma, Basal Cell (BCC)	2
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	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 / Glioblastoma, Adult / Gliosarcoma, Adult / Recurrent Brain Tumor, Adult	1
2	Completed	Treatment	Adult Medulloblastoma	1
2	Completed	Treatment	Basal Cell Nevus Syndrome / Gorlin's Syndrome	2
2	Completed	Treatment	Cancer of the Skin / Cutaneous Malignancy / Locally advanced basal cell carcinoma (BCC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	150 mg/1
Capsule	Oral
Capsule, coated	Oral	150 mg
Capsule	Oral	150 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9278961	No	2016-03-08	2028-12-15
US7888364	No	2011-02-15	2028-11-11
US9790183	No	2005-09-02	2025-09-02

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

Targets

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insights and accelerate drug research.

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Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	7	N/A	N/A	A31142
Ki (nM)	16.2	N/A	N/A	A31143

Details1. 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

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

Details1. Cytochrome P450 2C9

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

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]
Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]
Vismodegib FDA Label [File]

Details2. Cytochrome P450 3A4

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

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]

Details3. Cytochrome P450 2C8

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

Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]

Details4. Cytochrome P450 2C19

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

Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [Article]
Vismodegib [File]

Carriers

Property	Measurement	pH	Temperature (°C)	References
Kd (nM)	1.20E+05	N/A	N/A	A28805
Kd (nM)	1.30E+05	N/A	N/A	A28805
Kd (nM)	5.50E+03	N/A	N/A	A28805
Kd (nM)	6.00E+03	N/A	N/A	A28805

Details1. 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

Details2. Alpha-1-acid glycoprotein 1

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

Details1. P-glycoprotein 1

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

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]

Details2. ATP-binding cassette sub-family G member 2

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

Vismodegib

Identification

Structure for Vismodegib (DB08828)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

Enzymes

References

References

References

References

Carriers

Transporters

References