Bortezomib

Key Terms: Antineoplastic, Enzyme, Peripheral neuropathy, Saline.

Definition

Bortezomib is an man-made antineoplastic drug used to treat multiple myeloma.

Purpose

Bortezomib is used to treat individuals with multiple myeloma that has continued to grow and spread after being treated with least two other types of therapy. Standard treatments for multiple myeloma include a combination of steroid drugs, chemotherapy, and stem cell transplantation.

Multiple myeloma is the second most common blood cancer in the United States, with about 14,600 new cases diagnosed each year. It arises in the plasma cells of the bone marrow and causes multiple tumors. Plasma cells, sometimes called myeloma cells, are part of the body's immune system. When they become cancerous, they multiply uncontrollably and produce abnormal proteins that interfere with the growth and functions of normal cells. The also can spread to other parts of the body.

Description

Bortezomib is a type of drug called a protease inhibitor. It sold in the United States under the brand name Velcade by Millennium Pharmaceuticals. It was approved for use by the United States Food and Drug Administration (FDA) in May 2003. Generic substitutes are not available.

Proteasome is an enzyme complex that plays a role in many metabolic processes of the cell related to cell growth. Bortezomib blocks the production of proteasome. By doing this, it slows cell growth and can cause the cells to die. Although bortezomib also affects healthy cells, it has a much greater effect on cancer cells, because they are rapidly so growing. As a result, tumor growth can be slowed.

Recommended Dosage

Bortezomib is given in a hospital or clinic by injection into a vein. It is a white powder that comes in a single-dose vial to which saline is added just before use. The therapeutic administration cycle is three weeks. This cycle can be repeated up to eight times. Individuals are given a dose based on body size on days one, four, eight and 11. This is followed by a 10-day rest period, after which the cycle is repeated. Regular monitoring of blood count is done throughout treatment. The dose may be adjusted based on laboratory results and side effects, but the timing of administration remains the same.

Precautions

Bortezomib should not be given to individuals who have shown hypersensitivity to bortezomib, boron, or mannitol. Individuals who have numbness, pain, burning, or tingling their hands and feet (peripheral neuropathy) may not be good candidates to receive this drug, because bortezomib causes or enhances these symptoms. If symptoms become intense enough, the therapy must be stopped. Bortezomib also causes or enhances low blood pressure and can worsen congestive heart failure. Individuals with these conditions may need dosage adjustment. Individuals with liver or kidney disease may also need to have their dosage reduced.

Bortezomib can cause harm to the developing fetus and should not be used by pregnant women. Women should use birth control for 12 months after receiving this therapy. It has not been established whether this therapy is safe to use in breastfeeding women. A pediatric dose has not been established.

Side Effects

Side effects are many and varied. The most common include:

• peripheral neuropathy; tingling, pain and loss of sensation or numbness in the hands and feet
• low blood pressure (hypotension) and dizziness, especially when going from lying or sitting to standing
• nausea, vomiting, diarrhea, dehydration severe enough to require medication and/or fluid and electrolyte replacement
• frequent bleeding; decrease in the ability of blood to clot (thrombocytopenia) caused by death of blood platelets and low platelet count
• tumor lysis syndrome that causes chemical imbalances in the blood
• fever
• increased susceptibility to infection
• weakness, fatigue, fainting, light-headedness, blurred vision; individuals should avoid driving and operating machinery.

Other side effects that may occur include:

• anxiety, agitation, or insomnia
• muscle and joint aches or cramps
• cough
• rash
• headache
• decreased appetite

Interactions

It is important to tell the physician about all prescription medications, over-the-counter medications, and herbal or alternative remedies that are being taken before treatment with bortezomib is begun. Although formal drug interaction studies have not been completed, a number of drugs may interact with bortezomib, especially those that lower blood pressure or cause symptoms of peripheral neuropathy. These include:

• amiodarone (Cordarone, Pacerone)
• blood thinners (warfarin, Coumadin, Plavix)
• bosentan (Tracleer)
• carbamazepine
• cimetidine (Tagamet)
• clarithromycin (Biaxin)
• erythromycin
• fluoxetine (Prozac, Sarafem)
• fluvoxamine (Luvox)
• nefazodone
• phenytoin (Dilantin)
• rifabutin (Mycobutin)
• rifampin (Rifadin, Rimactane)
• St. John's wort (herbal treatment)
• medications to treat fungal infections
• some diabetes medications

—Tish Davidson, A. M.

Brand names: Velcade™

Chemical formula:

Drug Forms:
• Bortezomib injection (below)
• Bortezomib Solution for injection

Español:
• Inyección de bortezomib
• Bortezomib, Solución para inyección

Bortezomib injection

What is bortezomib injection?

BORTEZOMIB (Velcade®) targets specific proteins within cancer cells and stops the cancer cells from growing. Bortezomib is used to treat certain cancers including multiple myeloma. This drug might be used to treat other cancers. Generic bortezomib injections are not available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• dental disease
• heart disease
• history of low blood pressure or taking medicines to lower blood pressure
• receiving dialysis
• liver disease
• low blood counts including low white blood cell, platelet, or hemoglobin counts
• orthostatic hypotension (severe dizziness or fainting upon standing)
• peripheral neuropathy or related conditions
• an unusual reaction to bortezomib, mannitol, boron, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should this medicine be used?

Bortezomib is given as an injection into your vein. It is usually administered in a hospital or clinic setting by a specially trained health care professional. You will be given an injection twice a week for 2 weeks, and this course will be repeated after a 10 day rest period depending upon your laboratory results.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What if I miss a dose?

What drug(s) may interact with bortezomib?

• amiodarone
• bosentan
• carbamazepine
• cimetidine
• clarithromycin
• erythromycin
• fluoxetine
• fluvoxamine
• herbal products containing St. John's wort
• medicines for diabetes
• medicines to treat or prevent blood clots
• medicines to treat HIV infection
• nefazodone
• phenytoin
• rifabutin
• rifampin
• some medicines used to treat fungal infections (fluconazole, itraconazole, ketoconazole, voriconazole)

Talk to your prescriber or health care professional before taking any of these medicines:
• aspirin
• acetaminophen
• ibuprofen
• naproxen
• ketoprofen

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking bortezomib?

Visit your prescriber or health care professional for checks on your progress. You will need to have regular blood checks. The side effects of bortezomib can continue after you finish your treatment; report side effects promptly.

You may experience vomiting or diarrhea during bortezomib therapy. Drink plenty of fluids. If these side effects occur, talk to your health care provider to see what you should do to manage these effects.

Bortezomib may make you feel generally unwell and/or weak. This is not uncommon. Report any side effects as above, but continue your course of medicine even though you feel ill, unless your prescriber or health care professional tells you to stop.

Bortezomib may decrease your body's ability to fight infections. Call your prescriber or health care professional if you have a fever, chills, sore throat, or other symptoms of a cold or flu. Do not treat these symptoms yourself. Try to avoid being around people who are sick. Bortezomib may increase your risk to bruise or bleed. Call your prescriber or health care professional if you notice any unusual bleeding. Be careful not to cut, bruise or injure yourself because you may get an infection and bleed more than usual.

Avoid taking aspirin, acetaminophen (Tylenol®), ibuprofen (Advil®), naproxen (Aleve®), or ketoprofen (Orudis® KT) products as these may hide a fever, unless instructed to by your prescriber or health care professional.

Bortezomib is associated with fatigue, dizziness, light-headedness, fainting and blurred vision. Avoid driving or operating machinery until you know how bortezomib may affect you.

Be careful brushing and flossing your teeth or using a toothpick while receiving bortezomib because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are taking or have taken bortezomib.

Although it has not been proven, bortezomib may decrease fertility in both men and women. Discuss options with your health care provider. In addition, bortezomib can harm an unborn child if taken during pregnancy. Women who are able to have children should avoid becoming pregnant while taking bortezomib.

If you are going to have surgery, tell your prescriber or health care professional that you are taking or have taken bortezomib.

What side effects may I notice from receiving bortezomib?

Side effects that you should report to your prescriber or health care professional as soon as possible:
• low blood counts - bortezomib may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
• signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
• signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, nosebleeds
• signs of decreased red blood cells - unusual weakness or tiredness, fainting spells, lightheadedness
• changes in vision
• diarrhea
• dizziness upon standing
• fainting
• fluid retention
• numbness, pain, or a burning feeling in the hands or feet
• seizures
• shortness of breath
• skin rash
• vomiting

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• anxiety
• bone aches and pain
• decreased appetite
• dizziness
• fatigue
• headache
• itching
• muscle aches and pain
• muscle cramps
• nausea
• weakness

Where can I keep my medicine?

This does not apply. You will only receive bortezomib injection in a hospital or clinic setting.

Last updated: 3/22/2005 11:23:00 AM

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Bortezomib

Systematic (IUPAC) name
[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
Identifiers
CAS number	179324-69-7
ATC code	L01XX32
PubChem	387447
DrugBank	APRD00828
ChemSpider	343402
Chemical data
Formula	C19H25BN4O4
Mol. mass	384.237 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	n/a
Protein binding	83%
Metabolism	Hepatic, CYP extensively involved
Half life	9 to 15 hours
Excretion	?
Therapeutic considerations
Licence data	EU EMEA:link, US FDA:link
Pregnancy cat.	D(US)
Legal status	℞ Prescription only
Routes	Intravenous
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Bortezomib (INN, originally codenamed PS-341; marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma^[1] and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Contents 1 History 2 Pharmacology 2.1 Structure 2.2 Mechanism 2.3 Pharmacodynamics 3 Costs 3.1 UK 4 Adverse effects 5 Drug interactions 6 Further improvement of anticancer potency 7 References 8 External links

History

Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought by Millennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and was still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib. In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.^[2]

Pharmacology

Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic threonine residue whose activity is blocked by the presence of bortezomib.

Structure

The drug is a tripeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with boronic acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, but as in vitro peptide synthesis proceeds C-terminus to N-terminus, peptide drugs are illustrated C to N, as in this case.

Mechanism

The boron atom in bortezomib binds the catalytic site of the 26S proteasome^[3] with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins, and also cleanses the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways.

Pharmacodynamics

Bortezomib is rapidly cleared following intravenous administration.^[4] Peak concentrations are reached at about 30 minutes. Drug levels can no longer be measured after an hour. Pharmacodynamics are measured by measuring proteasome inhibition in peripheral blood mononuclear cells. The much greater sensitivity of myeloma cell lines and mantle cell lines to proteasome inhibition compared with normal peripheral blood mononuclear cells and most other cancer cell lines is poorly understood.

Costs

UK

NICE recommended against Velcade in Oct 2006 due to its cost.^[5]

The company proposed a cost reduction for multiple myeloma,^[6] and this was taken up in the UK.^[7]

Adverse effects

Bortezomib is associated with peripheral neuropathy in 30% of patients; occasionally, it can be painful. This can be worse in patients with pre-existing neuropathy. In addition, myelosuppression causing neutropenia and thrombocytopenia can also occur and be dose-limiting. However, these side effects are usually mild relative to bone marrow transplantation and other treatment options for patients with advanced disease. Bortezomib is associated with a high rate of shingles.^[8]

GI effects and asthenia are the most common adverse events.^[9]

Drug interactions

Green tea extract Epigallocatechin gallate(EGCG), which had been expected to have a synergistic effect, was found by Encouse B. Golden, et al. to reduce the effectiveness of bortezomib.^{[10][11][12][13]}

Further improvement of anticancer potency

Laboratory studies and clinical trials are investigating whether it might be possible to further increase the anticancer potency of bortezomib by combining it with novel types of other pharmacologic agents. For example, clinical trials have indicated that the addition of thalidomide, lenalidomide, inhibitors of vascular endothelial growth factor (VEGF), or arsenic trioxide might be beneficial.^[14][15] In laboratory studies, it was found that bortezomib killed multiple myeloma cells more efficiently when combined, for example, with histone deacetylase inhibitors,^[16] thapsigargin,^[17] or celecoxib.^[18] However, the therapeutic efficacy of any of these latter combinations has not yet been confirmed in cancer patients.

References

1. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
2. ^ Adams J, Kauffman M (2004). "Development of the Proteasome Inhibitor Velcade (Bortezomib)". Cancer Invest 22 (2): 304–11. doi:10.1081/CNV-120030218. PMID 15199612. 
3. ^ Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838–42. doi:10.1038/sj.leu.2404528. PMID 17268529. 
4. ^ Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (2003). "The proteasome as a target for cancer therapy". Clin Cancer Res 9 (17): 6316–25. PMID 14695130. 
5. ^ "NHS watchdog rejects cancer drug". BBC News UK. 20 October 2006. http://news.bbc.co.uk/1/hi/health/6069386.stm. Retrieved 2009-08-14. 
6. ^ "Summary of VELCADE Response Scheme". http://www.nice.org.uk/nicemedia/pdf/MyelomaDofHSummaryResponderScheme.pdf. Retrieved 2009-08-14. 
7. ^ "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 21 January 2009. http://www.europharmatoday.com/2009/01/more-velcadestyle-risksharing-in-the-uk.html. Retrieved 2009-08-14. 
8. ^ Oakervee HE, Popat R, Curry N, et al. (2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". Br J Haematol 129 (6): 755–62. doi:10.1111/j.1365-2141.2005.05519.x. PMID 15953001. 
9. ^ Highlights Of Prescribing Information
10. ^ "Cancer drug benefits could be negated by healthy tea treatment". Belfast Telegraph. 3 February 2009. http://www.belfasttelegraph.co.uk/news/health/cancer-drug-benefits-could-be-negated-by-healthy-tea-treatment-14168666.html. Retrieved 2009-08-14. 
11. ^ http://www.news-medical.net/?id=45529 "Green tea may counteract anticancer effects of cancer therapy, bortezomib (Velcade)"
12. ^ http://www.ecancermedicalscience.com/news-insider-news.asp?itemId=414
13. ^ Golden EB, et al. (2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors". Blood. doi:10.1182/blood-2008-07-171389. PMID 19190249. 
14. ^ Anargyrou K et al. (2008). "Novel anti-myeloma agents and angiogenesis". Leuk Lymphoma 49 (4): 677–689. doi:10.1080/10428190701861686. PMID 18398734. 
15. ^ Richardson PG et al. (2005). "Novel biological therapies for the treatment of multiple myeloma". Best Pract Res Clin Haematol 18 (4): 619–634. doi:10.1016/j.beha.2005.01.010. PMID 16026741. 
16. ^ Nawrocki ST et al. (2006). "Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells". Cancer Res 66 (7): 3773–3781. doi:10.1158/0008-5472.CAN-05-2961. PMID 16585204. 
17. ^ Nawrocki ST et al. (2005). "Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis". Cancer Res 65 (24): 11658–11666. doi:10.1158/0008-5472.CAN-05-2370. PMID 16357177. 
18. ^ Kardosh A et al. (2008). "Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib". Cancer Res 68 (3): 843–851. doi:10.1158/0008-5472.CAN-07-5555. PMID 18245486. 

External links

• Myeloma patients campaigning for access to a life prolonging cancer drug
• Millennium Pharmaceuticals website on Velcade
• Multiple Myeloma Research Foundation article on Velcade
• International Myeloma Foundation article on Velcade
• U.S. Food and Drugs Administration on Velcade
• Dedicated website for European audience
• Presentation at 2006 ASCO of the PINNACLE Study on MCL by Dr. Goy, with video/slides

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