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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