Vismode gib

7/30/2019 Vismode gib

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A Novel Breakthrough for BCC


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Approval status : jan 2012

Treatment area:

adults with metastatic basal cell carcinoma.

locally advanced basal cell carcinoma that has recurred

following surgery .Pts who are not candidates for surgery or for radiation.


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IntroductionVismodegib is an inhibitor of the hedgehog (Hh) signalingpathway.

It is described chemically as 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

The molecular formula is C19H14Cl2N2O3S.

The molecular weight is 421.30 g/mol

The structural formula is:


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HEDGEHOG SIGNALLING PATHWAY

Activation of the hedgehog pathway has beenimplicated in the development ofcancers in various organs

including brain, lung, mammary gland, prostate and skin.
http://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Mammary_glandhttp://en.wikipedia.org/wiki/Prostatehttp://en.wikipedia.org/wiki/Skinhttp://en.wikipedia.org/wiki/Skinhttp://en.wikipedia.org/wiki/Prostatehttp://en.wikipedia.org/wiki/Mammary_glandhttp://en.wikipedia.org/wiki/Lunghttp://en.wikipedia.org/wiki/Brainhttp://en.wikipedia.org/wiki/Cancer


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Clinical pharmacologyMechanism of action:-

The substance acts as a cyclopamine-competitiveantagonist of the smoothened receptor (SMO) which ispart of the hedgehog signaling pathway.

SMO inhibition causes the transcription factors GLI1 andGLI2 to remain inactive, which prevents the expression oftumor mediating genes within the hedgehog pathway.

This pathway is pathogenetically relevant in more than90% of basal-cell carcinomas
http://en.wikipedia.org/wiki/Cyclopaminehttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Smoothenedhttp://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/GLI1http://en.wikipedia.org/wiki/GLI2http://en.wikipedia.org/wiki/GLI2http://en.wikipedia.org/wiki/GLI2http://en.wikipedia.org/wiki/GLI1http://en.wikipedia.org/wiki/GLI1http://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/Hedgehog_signaling_pathwayhttp://en.wikipedia.org/wiki/Smoothenedhttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Cyclopamine


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Clinical pharmacologyPharmacokinetics:

Absorption

It is a highly permeable compound with low aqueoussolubility.

Capsule may be taken without regard to meals bcoz thesystemic exposure of vismodegib at steady state is notaffected by food.

Distribution

Vol. of distribution ranges from 16.4 to 26.6 L.

plasma protein binding is greater than 99%.

It binds to both human serum albumin and -1-acid

glycoprotein.


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Clinical pharmacologyMetabolism

Metabolic pathways include oxidation,

glucuronidation and pyridine ring clevage. It is eliminated via feces(82%) and urine(4.4%)

Plasma t1/2 is 4 days, after continuous daily dosing.


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Dosage and administration:

The recommended dose of vismodegib-150mg orally oncedaily

It may be taken with or without food.

Contraindications: None

Precautions:

Advise pts. Not to donate blood or blood products whilereceiving vismodegib and for atleast 7 months after its lastdose.

Vismodegib can cause embryo-fetal death or severe birth

defects.


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Adverse drug reactions

muscle spasms alopecia dysgeusia

weight loss fatiguenausea

Diarrheadecreased appetiteConstipationArthralgiasVomitingageusia

Most common adverse drug reactions were ( incidence>10%)

Amenorrhea:In clinical trials, a total of 3 of 10 pre-menopausal womendeveloped amenorrhea while receiving vismodegib


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Drug interactions

Effect of other drugs on Vismodegib :-

Drugs that inhibit Drug Transport Systems

It is substrate of the efflux transporter P-gp. When itis coadministered with drugs that inhibit P-gp (e.g.erythromycin, azithromycin), systemic exposure of

vismodegib and incidence of adverse events may be

increased.


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Drug interactions

Drugs that affect gastric PH

Drugs that alter the pH of the upper GI tract (e.g.proton pump inhibitors, H2-receptor antagonists,

and antacids) may alter the solubility ofvismodegib and reduce its bioavailability.

Effect of Vismodegib on other drugs:-

In vitro studies indicate that vismodegib is aninhibitor of CYP2C8, CYP2C9, CYP2C19 and thetransporter BCRP.


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Use in specific populationPregnancy- it is category D drug

it can cause fetal harm when administered to a pregnant

female based on its mechanism of action.

It is teratogenic in rats [ craniofacial anomalies, open

perineum absent or fused digits and fetal retardations]

Nursing mothers

It is not known whether vismodegib is excreted in human

breast milk.


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Use in specific population

Pediatric use

The safety and effectiveness have not been established

in pediatric pts. In repeat-dose toxicology studies in rats,

administration of oral vismodegib resulted in toxicities

in bone and teeth.


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Use in specific population

Females and males of Reproductive potential:- Females

determine the pregnancy status within 7days prior toinitiation of treatment.

Negative pregnancy test, highly effective contraceptionduring therapy & for 7months after last dose.

males

Should use condoms with spermicide, even after vasectomy.


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Use in specific populationHepatic impairment

The safety and effectiveness of Vismodegib have notbeen established in patients with hepatic impairment.

Renal impairment The safety and effectiveness of Vismodegib have not

been established in patients with renal impairment


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Vismode gib