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Bortezomib is a dipeptide boronic acid analog with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquitinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.
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Bortezomib is an anti-cancer drug and the first therapeutic proteasome inhibitor to be used in humans. Proteasomes are cellular complexes that break down proteins. The boron atom within bortezomib catalytically binds the active site of the 26S proteasome with high affinity and specificity, thereby resulting in cell cycle arrest and apoptosis. In normal cells, the proteasome is involved in degradation of ubiquitylated proteins that have been tagged for destruction because they are damaged or unneeded by the cell. In some cancers, the proteins that normally kill cancer cells are broken down too quickly. Bortezomib interrupts this process and lets those proteins kill the cancer cells. It is approved in the U.S. and Europe for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
Mechanism of Action of Bortezomib
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).
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Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent. The drug reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome by bortezomib prevents targeted proteolysis and causes disruption of normal homeostatic mechanisms, which can lead to cell death. In vitro studies indicate that bortezomib is cytotoxic to a variety of cancer cell types. Bortezomib has been shown to cause a delay in tumor growth in vivo in tumor models, including multiple myeloma.
Indications of Bortezomib
- Lymphoma
- Mantle Cell Lymphoma
- Multiple Myeloma
- Mantle Cell Lymphoma (MCL)
- Treatment of mantle cell lymphoma
- Treatment of multiple myeloma (who had previously responded to treatment with this drug and who have relapsed at least 6 months after completing treatment)
From FDA Level
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Bortezomib Accord as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
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Bortezomib Accord in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib Accord in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib Accord in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.
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Bortezomib Hospira as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
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Bortezomib Hospira in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib Hospira in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib Hospira in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.
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Bortezomib SUN as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
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Bortezomib SUN in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib SUN in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
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Bortezomib SUN in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.
Contra-Indications of Bortezomib
- Diabetes
- Extreme Loss of body water
- Decreased blood platelets
- Decreased neutrophils a type of white blood cell
- Peripheral pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">neuropathy
- The increased pressure of the pulmonary circulation
- Chronic heart failure
- Blood pressure drop upon standing
- Abnormally low blood pressure
- Pneumonia
- Interstitial pneumonitis
- Acute respiratory distress syndrome
- Blocked bowels with decreased peristaltic movement
- Liver problems
- Pregnancy
- A Mother who is producing milk and breastfeeding
- Brain-capillary leak syndrome
Dosages of Bortezomib
- Strengths: 3.5 mg
Lymphoma
Dosage in previously united mantle cell lymphoma
- 1.3 mg/m2 as a bolus IV injection twice weekly in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21)
For use in the treatment of release mantle cell lymphoma
- Usual dose: 1.3 mg/m2 as a bolus IV injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).
Multiple Myeloma
For use in the treatment previous treatment of multiple myeloma
- Usual dose: 1.3 mg/m2 administered as a 3 to 5 second bolus IV injection or subcutaneously in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles:
- In cycles 1 through 4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (days 1, 8, 22, and 29).
For use in the treatment of release multiple myeloma
- Usual dose: 1.3 mg/m2 as a bolus intravenous injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).
Side Effects of Bortezomib
The most common
- chest pain
- anxiety
- irregular heartbeat
- certainly hair loss
- a 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 Bortezomib
Bortezomib 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, felodipine)
- bupropion
- estrogen and estrogen-containing birth control (women)
- medications that promote loss of bone density (e.g., prednisone)
- testosterone and androgens (men)
- corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
- cyclosporine
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- losartan
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- montelukast
- norfloxacin
- ondansetron
- carbamazepine
- phenytoin
- 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)
- 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,
- trimethoprim
- other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- tetracycline
- tocilizumab
- vitamin C
Pregnancy & Lactation of Bortezomib
FDA Pregnancy Category D
Pregnancy
No studies have been conducted to determine the effect of bortezomib on an unborn baby if the medication is used during pregnancy. Women should avoid becoming pregnant while taking bortezomib. Men and women should use effective contraception during bortezomib treatment and for the 3 months following treatment. If you become pregnant while using this medication, contact your doctor immediately.
Lactation
It is not known if bortezomib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Women should not breast-feed while taking bortezomib.The safety and effectiveness of bortezomib have not been established for use by children and adolescents less than 18 years of age
References
