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Vemurafenib is a selective inhibitor of BRAF kinase that is used in the therapy of metastatic and advanced malignant melanoma. Vemurafenib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe cases of clinically apparent acute liver injury.
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Vemurafenib is an orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation. Approximately 90% of BRAF gene mutations involve a valine-to-glutamic acid mutation at residue 600 (V600E); the oncogene protein product, BRAF(V600E) kinase, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway. The BRAF(V600E) gene mutation has been found to occur in approximately 60% of melanomas and in about 8% of all solid tumors, including melanoma, colorectal, thyroid, and other cancers.
Vemurafenib is a type of targeted cancer drug called a cancer growth blocker. It stops cells producing a protein called BRAF, which makes some cancer cells grow and divide. About half (about 50%) of all melanomas make too much BRAF proteins. This is due to a change in the BRAF gene. Vemurafenib is a competitive kinase inhibitor with activity against BRAF kinase with mutations like V600E. It exerts its function by binding to the ATP-binding domain of the mutant BRAF.
Mechanism of Action of Vemurafenib
Vemurafenib causes programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK stepon the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation. Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.BRAF is an intermediary molecule in MAPK whose activation depends on ERK activation, elevation of cyclin D1 and cellular proliferation. The mutation V600E produces a constitutive form of BRAF. Vemurafenib has been shown to reduce all activation markers related to BRAF; in clinical trials, vemurafenib treatment showed a reduction of cytoplasmic phosphorylated ERK and a cell proliferation driven by Ki-67. Studies also reported a decrease in MAPK-related metabolic activity. All the different reports indicate that Vemurafenib generates an almost complete inhibition of the MAPK pathway.
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Cutaneous squamous cell carcinoma (cuSCC) has been reported in patients with metastatic melanoma and CRC treated with vemurafenib. Clinical findings indicate that cuSCC may be related to treatment with vemurafenib. In order to understand the potential mechanism by which vemurafenib treatment contributes to the development of cuSCC, vemurafenib was tested in vivo in the A431 cuSCC xenograft model. There was dose-dependent tumor growth stimulation of the xenograft tumors at doses higher than 25 mg/kg bid. The optimal dose of 75 mg/kg bid of vemurafenib caused a 103% induction of growth compared to the control (p=0.002). Immunohistochemistry showed staining of pERK only in the tumor samples treated with vemurafenib (75 mg/kg) as compared to the vehicle-treated control group. Combination studies of vemurafenib and a MEK inhibitor, RO5068760, were performed to confirm the inhibition of pERK.
Indications of Vemurafenib
- Metastatic Melanoma
- Unresectable Melanoma
- Refractory Erdheim-Chester disease
- Refractory Non-small cell lung cancer
- Vemurafenib is used for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation. Vemurafenib is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer
Contra Indication of Vemurafenib
- Diabetes
- High cholesterol
- Low amount of magnesium in the blood
- Low amount of phosphate in the blood
- Low amount of calcium in the blood
- Low amount of sodium in the blood
- The high amount of potassium in the blood
- Low amount of potassium in the blood
- Anemia
- Decreased Blood Platelets
- Decreased Neutrophils a Type of White Blood Cell
- High blood pressure
- Very Rapid Heartbeat – Torsades de Pointes
- prolonged QT interval on EKG
- Abnormal EKG with QT changes from Birth
- Hardening of the arteries due to plaque buildup
- Liver problems
- High Amount of jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">Bilirubin in the Blood
- High Blood Sugar
- Abnormal liver function tests
- Pregnancy
- A mother who is producing milk and breastfeeding
- Relapse of Hepatitis B Infection Symptoms
- Pancreatitis
Dosages of Vemurafenib
Strengths: 240 mg
Melanoma – Metastatic
- Maintenance dose: 960 mg orally every 12 hours with or without a meal
- Duration of therapy: Treat patients until disease progression or unacceptable toxicity occurs.
Side Effects of Vemurafenib
The most common
- chest pain
- certainly hair loss
- headache
- joint painPain
- dizziness
- nausea and vomiting
- Severe stomach ache
- epigastric pain,
- diarrhoea,
- anorexia,
- flatulence,
- headache,
- dizziness,
- fainting, fast or pounding heartbeats.
More common
- Fast or irregular heartbeat
- appetite loss
- changes in nails
- constipation
- fatigue
- fever
- Back pain
- dizziness
- headache
- increased cough
- Acid or sour stomach
- decreased appetite
- Agitation
- chest congestion
- chest pain
- cold sweats
- confusion
- decreased sexual ability or desire
- stomach or abdominal cramps, gas, or pain
- trouble sleeping
Less common
- bleeding gums
- blood in the urine or stools
- chest pain
- diarrhea
- Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
- difficulty in moving
- muscle stiffness
- redness of the face, neck, arms and occasionally, upper chest
- lack or loss of strength
- muscle spasm
- difficult or labored breathing
- dry mouth
- headache
- irritability
- lack or loss of strength
- loose stools
- loss of interest or pleasure
- muscle stiffness
- night sweats
- passing gas
- stomach discomfort, upset, or pain
- swollen joints
- trouble concentrating
- increased blood pressure
Drug Interactions of Vemurafenib
Vemurafenib may interact with following drugs, supplements & may change the efficacy of the drug
- alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
- “azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
- beta-blockers (e.g., atenolol, propranolol, metoprolol)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
- calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine,)
- carbamazepine
- chloroquine
- corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
- cyclosporine
- dantrolene
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delaviridine, efavirenz, etravirine, nevirapine)
- losartan
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mirtazapine
- montelukast
- norfloxacin
- ondansetron
- carbamazepine
- phenytoin
- progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
- proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
- sildenafil
- “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- tacrolimus
- tadalafil
- tamoxifen
- tetracycline
- theophylline
- tocilizumab
- tolterodine
- tramadol
- other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
- 5-HT3 antagonists (e.g., granisetron, ondansetron)
- tamsulosin
- tapentadol
- thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
- tramadol
- tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
- other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- tetracycline
- tocilizumab
- vandetanib
- vemurafenib
- trimethoprim
- vaccines
- warfarin
Pregnancy & Lactation
FDA Pregnancy Category C
Pregnancy
Vemurafenib may harm an unborn child. This medication should not be used during pregnancy unless the benefits outweigh the risks. Women who may become pregnant must use an effective birth control method while taking this medication and for at least 6 months after taking the last dose of medication. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if vemurafenib passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.
References
