Vismodegib

Vismodegib
Clinical data
Pronunciation	/ˌvɪsmoʊˈdɛɡɪb/; VIS-moh-DEG-ib
Trade names	Erivedge
Other names	GDC-0449, RG-3616
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN; US FDA: Vismodegib;
Pregnancy; category	AU: X (High risk); ;
Routes of; administration	By mouth
ATC code	L01XJ01 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: WARNINGRx-only; EU: Rx-only;
Pharmacokinetic data
Bioavailability	31.8%
Protein binding	>99%
Metabolism	<2% metabolised by CYP2C9, CYP3A4, CYP3A5
Elimination half-life	4 days (continuous use),; 12 days (single dose)
Excretion	Fecal (82%), Urinary (4.4%)
Identifiers
	IUPAC name 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide;
CAS Number	879085-55-9;
PubChem CID	24776445;
IUPHAR/BPS	6975;
DrugBank	DB08828;
ChemSpider	23337846;
UNII	25X868M3DS;
KEGG	D09992;
ChEBI	CHEBI:66903 ;
ChEMBL	ChEMBL473417;
CompTox Dashboard (EPA)	DTXSID40236689 ;
ECHA InfoCard	100.234.019
Chemical and physical data
Formula	C19H14Cl2N2O3S
Molar mass	421.29 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl;
	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); Key:BPQMGSKTAYIVFO-UHFFFAOYSA-N;

Vismodegib, sold under the brand name Erivedge, is a medication used for the treatment of basal-cell carcinoma (BCC).^[3] The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.^[4] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011^[update].^[5] The drug was developed by the biotechnology/pharmaceutical company Genentech.^[4]

Indication

Vismodegib is indicated for people with basal-cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.^[4]^[6]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the Hedgehog signaling pathway.^[5] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.^[7] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.^[8]

Side effects

In clinical trials, common side effects included gastrointestinal disorders (nausea, vomiting, diarrhoea, constipation), muscle spasms, fatigue, hair loss, and dysgeusia (distortion of the sense of taste).^[3]

Development

Vismodegib has undergone several promising phase I and phase II clinical trials for its use in treating medulloblastoma.^[9]

References

^ ^a ^b "Erivedge® (vismodegib)". Australian Prescribing Information, Australian Register of Therapeutic Goods (ARTG). Roche Products Pty Limited. 17 November 2022.
^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ ^a ^b ^c "Erivedge- vismodegib capsule". DailyMed. U.S. National Library of Medicine. 9 April 2019. Retrieved 8 January 2023.
^ ^a ^b ^c "FDA approves Erivedge (vismodegib) capsule, the first medicine for adults with advanced basal cell carcinoma". Roche. 30 January 2012. Retrieved 9 August 2020.
^ ^a ^b "Vismodegib". Molecule of the Month. Prous Science. June 2011. Archived from the original on 27 September 2011.
^ Lacroix M (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7. Archived from the original on 2015-06-26. Retrieved 2014-07-13.
^ "Vismodegib (GDC-0449) Smoothened Inhibitor". BioOncology. Genentech. Archived from the original on 4 June 2011.
^ Spreitzer H (4 July 2011). "Neue Wirkstoffe – Vismodegib". Österreichische Apothekerzeitung (in German) (14/2011): 10.
^ Li Y, Song Q, Day BW (July 2019). "Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis". Acta Neuropathologica Communications. 7 (1): 123. doi:10.1186/s40478-019-0773-8. PMC 6668073. PMID 31362788.

External links

"Vismodegib". Drug Information Portal. U.S. National Library of Medicine.

[Erivedge_PI-1] "Erivedge® (vismodegib)". Australian Prescribing Information, Australian Register of Therapeutic Goods (ARTG). Roche Products Pty Limited. 17 November 2022.

[FDA-AllBoxedWarnings-2] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[Erivedge_FDA_label-3] "Erivedge- vismodegib capsule". DailyMed. U.S. National Library of Medicine. 9 April 2019. Retrieved 8 January 2023.

[Roche_PR-4] "FDA approves Erivedge (vismodegib) capsule, the first medicine for adults with advanced basal cell carcinoma". Roche. 30 January 2012. Retrieved 9 August 2020.

[Prous-5] "Vismodegib". Molecule of the Month. Prous Science. June 2011. Archived from the original on 27 September 2011.

[6] Lacroix M (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7. Archived from the original on 2015-06-26. Retrieved 2014-07-13.

[7] "Vismodegib (GDC-0449) Smoothened Inhibitor". BioOncology. Genentech. Archived from the original on 4 June 2011.

[Spreitzer-8] Spreitzer H (4 July 2011). "Neue Wirkstoffe – Vismodegib". Österreichische Apothekerzeitung (in German) (14/2011): 10.

[9] Li Y, Song Q, Day BW (July 2019). "Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis". Acta Neuropathologica Communications. 7 (1): 123. doi:10.1186/s40478-019-0773-8. PMC 6668073. PMID 31362788.

[3]

[4]

[5]

[1]

[2]

[6]

[7]

[8]

[9]