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{{Short description|Chemical compound}}
{{Use dmy dates|date=December 2022}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox {{Drugbox
| verifiedrevid = 407341464 | verifiedrevid = 459493462
| IUPAC_name = propanoyl}amino)butyl]boronic acid
| image = Bortezomib.svg | image = Bortezomib.svg
| image_class = skin-invert-image
| image2 = Bortezomib-from-PDB-2F16-3D-balls.png
| alt =
| image2 = Bortezomib-based-on-PDB-2F16-Mercury-3D-balls.png
| image_class2 = bg-transparent
| alt2 =


<!--Clinical data--> <!--Clinical data-->
| tradename = Velcade | tradename = Velcade, others
| Drugs.com = {{drugs.com|monograph|bortezomib}} | Drugs.com = {{drugs.com|monograph|bortezomib}}
| MedlinePlus = a607007 | MedlinePlus = a607007
| DailyMedID = Bortezomib
| licence_EU = Velcade
| pregnancy_AU = C
| licence_US = Bortezomib
| routes_of_administration = ], ]
| pregnancy_US = D
| ATC_prefix = L01
| ATC_suffix = XG01

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Bortezomib Baxter (Baxter Healthcare Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=2 May 2024 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/bortezomib-baxter-baxter-healthcare-pty-ltd | access-date=5 October 2024}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Boruzu FDA label">{{cite web | title=Boruzu- bortezomib injection | website=DailyMed | date=27 September 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b92628dd-fa09-4c3a-b6a3-66426025807c | access-date=11 November 2024}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name=EMA2019 />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only | legal_status = Rx-only
| routes_of_administration = ]


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = n/a | bioavailability =
| protein_bound = 83% | protein_bound = 83%
| metabolism = ], ] extensively involved | metabolism = ], ] extensively involved
| elimination_half-life = 9 to 15 hours | elimination_half-life = 9 to 15 hours
| excretion = ? | excretion =


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 6391
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 179324-69-7 | CAS_number = 179324-69-7
| ATC_prefix = L01
| ATC_suffix = XX32
| PubChem = 387447 | PubChem = 387447
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 69G8BD63PP | UNII = 69G8BD63PP
| KEGG = D03150
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 325041 | ChEMBL = 325041
| PDB_ligand = BO2
| synonyms = PS-341


<!--Chemical data--> <!--Chemical data-->
| C=19 | H=25 | B=1 | N=4 | O=4 | C=19 | H=25 | B=1 | N=4 | O=4
| molecular_weight = 384.237 g/mol
| smiles = O=C(N(C(=O)N(B(O)O)CC(C)C)Cc1ccccc1)c2nccnc2 | smiles = O=C(N(C(=O)N(B(O)O)CC(C)C)Cc1ccccc1)c2nccnc2
| InChI = 1/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
| InChIKey = GXJABQQUPOEUTA-RDJZCZTQBH
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1 | StdInChI = 1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
Line 49: Line 74:
| StdInChIKey = GXJABQQUPOEUTA-RDJZCZTQSA-N | StdInChIKey = GXJABQQUPOEUTA-RDJZCZTQSA-N
}} }}
<!-- Definition and medical uses -->
'''Bortezomib''' (], originally codenamed '''PS-341'''; marketed as '''Velcade''' by ]) is the first therapeutic ] to be tested in humans. It is approved in the U.S. for treating relapsed ]<ref>Takimoto CH, Calvo E. in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) . 11 ed. 2008.</ref> and ]. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
'''Bortezomib''', sold under the brand name '''Velcade''' among others, is an ] used to treat ] and ].<ref name=AHFS2019>{{cite web |title=Bortezomib Monograph for Professionals |url=https://www.drugs.com/monograph/bortezomib.html |website=Drugs.com |access-date=13 October 2019 }}</ref> This includes multiple myeloma in those who have and have not previously received treatment.<ref name=EMA2019/> It is generally used together with other medications.<ref name=EMA2019/> It is given by injection.<ref name=AHFS2019/>

<!-- Side effects and mechanism -->
Common side effects include nausea, diarrhea, tiredness, ], fever, numbness, ], shortness of breath, rash and abdominal pain.<ref name=AHFS2019/> Other severe side effects include ], ], ], and ].<ref name=AHFS2019/><ref name=EMA2019/> It is in the class of medications known as ].<ref name=AHFS2019/> It works by inhibiting ]s, cellular complexes that break down proteins.<ref name=EMA2019/>

<!-- History and culture -->
Bortezomib was approved for medical use in the United States in 2003 and in the European Union in 2004.<ref name=AHFS2019/><ref name=EMA2019>{{cite web |title=Velcade EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/velcade |website=] (EMA) |access-date=13 October 2019 |date=17 September 2018}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a ].<ref>{{cite web | title=2022 First Generic Drug Approvals | website=U.S. ] (FDA) | date=3 March 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003602/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref>

==Medical use==
Two open-label trials established the efficacy of bortezomib (with or without ]) on days 1,4,8, and 11 of a 21-day cycle for a maximum of eight cycles in heavily pretreated people with relapsed/refractory multiple myeloma.<ref name=Curran2009>{{cite journal | vauthors = Curran MP, McKeage K | title = Bortezomib: a review of its use in people with multiple myeloma | journal = Drugs | volume = 69 | issue = 7 | pages = 859–88 | year = 2009 | pmid = 19441872 | doi = 10.2165/00003495-200969070-00006 | url = http://adisonline.com/drugs/abstract/2009/69070/Bortezomib__A_Review_of_its_Use_in_Patients_with.6.aspx | access-date = 26 March 2010 | url-status = dead | archive-url = https://web.archive.org/web/20111008153521/http://adisonline.com/drugs/abstract/2009/69070/Bortezomib__A_Review_of_its_Use_in_Patients_with.6.aspx | archive-date = 8 October 2011 }}</ref> The phase III demonstrated the superiority of bortezomib over a high-dose dexamethasone regimen (e.g. median ] 6.2 vs 3.5 months, and 1-year survival 80% vs 66%).<ref name=Curran2009/> New studies show that bortezomib may potentially help recover from vincristine treatment in treating acute lymphoblastic leukemia, when replacing vincristine in the process.<ref name="pmid31233464">{{cite journal | vauthors = Joshi J, Tanner L, Gilchrist L, Bostrom B | title = Switching to Bortezomib may Improve Recovery From Severe Vincristine Neuropathy in Pediatric Acute Lymphoblastic Leukemia | journal = Journal of Pediatric Hematology/Oncology | volume = 41 | issue = 6 | pages = 457–462 | date = August 2019 | pmid = 31233464 | doi = 10.1097/MPH.0000000000001529 | s2cid = 195357104 }}</ref>

Bortezomib was also evaluated together with other drugs for the treatment of multiple myelomas in adults. It was seen that bortezomib plus ] plus ] as well as bortezomib plus ] and ] may result in a large increase in the progression-free survival.<ref>{{cite journal | vauthors = Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, Ocheni S, Theurich S, Kuhr K, Scheckel B, Adams A, Skoetz N | display-authors = 6 | title = Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31765002 | doi = 10.1002/14651858.CD013487 | pmc = 6876545 | collaboration = Cochrane Haematology Group }}</ref>

==Adverse effects==
] effects and ] are the most common adverse events.<ref>{{Cite web|url=http://www.velcade.com/full_prescrib_velcade.pdf|archiveurl=https://web.archive.org/web/20090219102450/http://www.velcade.com/full_prescrib_velcade.pdf|url-status=dead|title=Highlights Of Prescribing Information<!-- Bot generated title -->|archivedate=19 February 2009|accessdate=19 December 2022}}</ref> Bortezomib is associated with ] in 30% of people resulting in pain. This can be worse in people with pre-existing ]. In addition, ] causing ] and ] can also occur and be dose-limiting. However, these ] are usually mild relative to ] and other treatment options for people with advanced disease. Bortezomib is associated with a high rate of ],<ref name="pmid15953001">{{cite journal | vauthors = Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD | display-authors = 6 | title = PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma | journal = British Journal of Haematology | volume = 129 | issue = 6 | pages = 755–62 | date = June 2005 | pmid = 15953001 | doi = 10.1111/j.1365-2141.2005.05519.x | s2cid = 34591121 | doi-access = free }}</ref> although ] ] can reduce the risk of this.<ref name="pmid19406726">{{cite journal | vauthors = Pour L, Adam Z, Buresova L, Krejci M, Krivanova A, Sandecka V, Zahradova L, Buchler T, Vorlicek J, Hajek R | display-authors = 6 | title = Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib | journal = Clinical Lymphoma & Myeloma | volume = 9 | issue = 2 | pages = 151–3 | date = April 2009 | pmid = 19406726 | doi = 10.3816/CLM.2009.n.036 }}</ref>

Ocular side effects such as chalazion or hordeolum (stye) may be more common in women and have led to discontinuation of treatment.<ref>{{cite journal | vauthors = Dennis M, Maoz A, Hughes D, Sanchorawala V, Sloan JM, Sarosiek S | title = Bortezomib ocular toxicities: Outcomes with ketotifen | journal = American Journal of Hematology | volume = 94 | issue = 3 | pages = E80–E82 | date = March 2019 | pmid = 30575098 | doi = 10.1002/ajh.25382 | doi-access = free }}</ref> Acute interstitial nephritis has also been reported.<ref>{{cite journal | vauthors = Cheungpasitporn W, Leung N, Rajkumar SV, Cornell LD, Sethi S, Angioi A, Fervenza FC | title = Bortezomib-induced acute interstitial nephritis | journal = Nephrology, Dialysis, Transplantation | volume = 30 | issue = 7 | pages = 1225–9 | date = July 2015 | pmid = 26109684 | doi = 10.1093/ndt/gfv222 | doi-access = free }}</ref>

==Drug interactions==
Polyphenols derived from green tea extract including ] (EGCG), which were expected to have a synergistic effect, instead were found to reduce the effectiveness of bortezomib in cell culture experiments.<ref>{{cite journal | vauthors = Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schönthal AH | display-authors = 6 | title = Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors | journal = Blood | volume = 113 | issue = 23 | pages = 5927–37 | date = June 2009 | pmid = 19190249 | doi = 10.1182/blood-2008-07-171389 | doi-access = free }}</ref>


==Origin and Development==
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 ] 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 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 ] (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.<ref name="pmid15199612">{{cite journal | author = Adams J, Kauffman M | title = Development of the Proteasome Inhibitor Velcade (Bortezomib) | journal = Cancer Invest | volume = 22 | issue = 2 | pages = 304–11 | year = 2004 | pmid = 15199612 | doi = 10.1081/CNV-120030218}}</ref>
Another commercially available bortezomib product - Bortenat (Natco Pharma, India), reportedly contains substantially more active entity than declared, potentially and even more resulting in increase toxicity. Moreover, Bortenat has some other chemical and formulation deviations from the registered ethic product Velcade (Millennium Pharmaceuticals and Janssen-Cilag), with unclear clinical impact.<ref name="S. Byrn">{{cite journal | author = Stephen R.Byrn et al | title = Analysis of two commercially available bortezomib products: differences in assay of active agent and impurity profile | journal = AAPS PharmSciTech | issue = april 1| year = 2011}}</ref>
==Pharmacology== ==Pharmacology==
] proteasome. The bortezomib molecule is in the center colored by atom type (boron = pink, carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic ] residue whose activity is blocked by the presence of bortezomib.]] ] proteasome. The bortezomib molecule is in the center colored by atom type (boron = pink, carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic ] residue whose activity is blocked by the presence of bortezomib.]]


===Structure=== === Structure ===
The drug is an N-protected ] and can be written as Pyz-Phe-boroLeu, which stands for ], ] and ] with a ] instead of a ]. Peptides are written N-terminus to C-terminus, and this convention is used here even though the "C-terminus" is a boronic acid instead of a carboxylic acid. The drug is an N-protected ] and can be written as Pyz-Phe-boroLeu, which stands for ], ] and ] with a ] instead of a ].


===Mechanism=== ===Mechanism===
The ] atom in bortezomib binds the catalytic site of the ]<ref name="pmid17268529">{{cite journal |author=Bonvini P, Zorzi E, Basso G, Rosolen A |title=Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma |journal=Leukemia |volume=21 |issue=4 |pages=838–42 |year=2007 |pmid=17268529 |doi=10.1038/sj.leu.2404528}}</ref> 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. The ] atom in bortezomib is proposed to bind the catalytic site of the ]<ref name="pmid17268529">{{cite journal | vauthors = Bonvini P, Zorzi E, Basso G, Rosolen A | title = Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma | journal = Leukemia | volume = 21 | issue = 4 | pages = 838–42 | date = April 2007 | pmid = 17268529 | doi = 10.1038/sj.leu.2404528 | doi-access = free }}</ref> with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ] proteins, and also rids the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role for the proteasome 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, thereby triggering programmed cell death in neoplastic cells. Bortezomib causes a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome.<ref name="pmid23308178">{{cite journal | vauthors = Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD | display-authors = 6 | title = Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e53263 | year = 2013 | pmid = 23308178 | pmc = 3538785 | doi = 10.1371/journal.pone.0053263 | bibcode = 2013PLoSO...853263G | doi-access = free }}</ref> Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug.


===Pharmacokinetics / Pharmacodynamics=== ===Pharmacokinetics and pharmacodynamics===
After subcutaneous administration, peak plasma levels are ~25-50 nM and this peak is sustained for 1-2 hrs. After intravenous injection, peak plasma levels are ~500 nM but only for ~5 minutes, after which the levels rapidly drop as the drug distributes to tissues (volume of distribution is ~500 L).<ref>{{cite journal | vauthors = Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, Burris H, Venkatakrishnan K, Neuwirth R, Riordan WJ, Karol M, von Moltke LL, Acharya M, Zannikos P, Keith Stewart A | display-authors = 6 | title = Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma | journal = Cancer Chemotherapy and Pharmacology | volume = 67 | issue = 1 | pages = 57–67 | date = January 2011 | pmid = 20306195 | pmc = 3951913 | doi = 10.1007/s00280-010-1283-3 }}</ref><ref>{{cite journal | vauthors = Voorhees PM, Dees EC, O'Neil B, Orlowski RZ | title = The proteasome as a target for cancer therapy | journal = Clinical Cancer Research | volume = 9 | issue = 17 | pages = 6316–25 | date = December 2003 | pmid = 14695130 }}</ref> Both routes provide equal drug exposures and generally comparable therapeutic efficacy. Elimination half life is 9–15 hours and the drug is primarily cleared by hepatic metabolism.<ref>{{cite journal | vauthors = Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL | display-authors = 6 | title = Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study | journal = The Lancet. Oncology | volume = 12 | issue = 5 | pages = 431–40 | date = May 2011 | pmid = 21507715 | doi = 10.1016/s1470-2045(11)70081-x }}</ref>
Bortezomib is rapidly cleared following intravenous administration.<ref>{{cite journal |author=Voorhees PM, Dees EC, O'Neil B, Orlowski RZ |title=The proteasome as a target for cancer therapy |journal=Clin Cancer Res |volume=9 |issue=17 |pages=6316–25 |year=2003 |pmid=14695130 |doi=}}</ref> Peak concentrations are reached at about 30 minutes. Drug levels can no longer be measured after an hour. ] 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.


The ] of bortezomib are determined by quantifying proteasome inhibition in peripheral blood mononuclear cells taken from people receiving the drug.
==Costs==
===UK===
] recommended against Velcade in Oct 2006 due to its cost.<ref>{{cite web|url=http://news.bbc.co.uk/1/hi/health/6069386.stm | title=NHS watchdog rejects cancer drug | accessdate=2009-08-14 | publisher=BBC News UK | date=20 October 2006}}</ref>


==History==
The company proposed a cost reduction for multiple myeloma,<ref>{{cite web|url=http://www.nice.org.uk/nicemedia/pdf/MyelomaDofHSummaryResponderScheme.pdf | title=Summary of VELCADE Response Scheme | accessdate=2009-08-14}}</ref> and this was taken up in the UK.<ref>{{cite web|url=http://www.europharmatoday.com/2009/01/more-velcadestyle-risksharing-in-the-uk.html | title=More Velcade-Style Risk-Sharing In The UK? | accessdate=2009-08-14 | publisher = Euro Pharma Today | date = 21 January 2009}}</ref>
Bortezomib was originally made in 1995 at Myogenics. The drug (PS-341) was tested in a small Phase I clinical trial on people with ]. It was brought to further clinical trials by ] in October 1999.<ref>{{Cite journal| vauthors = Larkin M |date=November 1999|title=(In)famous trials brought to life|journal=The Lancet|volume=354|issue=9193|pages=1915|doi=10.1016/s0140-6736(05)76886-0|s2cid=53301933|issn=0140-6736}}</ref>


In May 2003, bortezomib (marketed as Velcade by Millennium Pharmaceuticals Inc.) was approved in the United States by the ] (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.<ref name="pmid15199612">{{cite journal | vauthors = Adams J, Kauffman M | title = Development of the proteasome inhibitor Velcade (Bortezomib) | journal = Cancer Investigation | volume = 22 | issue = 2 | pages = 304–11 | year = 2004 | pmid = 15199612 | doi = 10.1081/CNV-120030218 | s2cid = 23644211 }}</ref><ref>{{cite web | title=Drug Approval Package: Velcade (Bortezomib) NDA #021602 | website=U.S. ] (FDA) | date=13 May 2003 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21602_Velcade.cfm | archive-url=https://web.archive.org/web/20191205163541/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21602_Velcade.cfm | archive-date=5 December 2019 | url-status=live | access-date=5 December 2019}} {{PD-notice}}</ref> In 2008, bortezomib was approved in the United States for initial treatment of people with multiple myeloma.<ref name="FDA PR 2008">{{cite press release | url = https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm094633.htm | title = Velcade (bortezomib) is Approved for Initial Treatment of Patients with Multiple Myeloma | date = 23 June 2008 | publisher = U.S. ] (FDA) | archive-url = https://web.archive.org/web/20111201193227/https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm094633.htm | archive-date = 1 December 2011 | url-status = dead | access-date = 5 December 2019 }} {{PD-notice}}</ref> Bortezomib was previously approved in 2005, for the treatment of people with multiple myeloma who had received at least one prior therapy and in 2003, for the treatment of more refractory multiple myeloma.<ref name="FDA PR 2008" />
==Adverse effects==
Bortezomib is associated with ] in 30% of patients; occasionally, it can be painful. This can be worse in patients with pre-existing neuropathy. In addition, ] causing ] and ] can also occur and be dose-limiting. However, these side effects are usually mild relative to ] and other treatment options for patients with advanced disease. Bortezomib is associated with a high rate of ],<ref name="pmid15953001">{{cite journal | author=Oakervee HE, Popat R, Curry N, ''et al.'' | title=PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma | journal=Br J Haematol | volume=129 | issue=6 | pages=755–62 | year=2005 | pmid=15953001 | doi=10.1111/j.1365-2141.2005.05519.x}}</ref> although prophylactic ] can reduce the risk of this.<ref name="pmid19406726">{{cite journal | author=Pour L., Adam Z., Buresova L., ''et al.'' | title=Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib | journal=Clinical Lymphoma & Myeloma | volume=9 | issue=2 | pages=151–3 | year=2009 | pmid=19406726 | doi=10.3816/CLM.2009.n.036}}</ref>


The 2008 approval was based on an international, multicenter, open label, active-control trial in previously untreated people with symptomatic multiple myeloma.<ref name="FDA PR 2008" /> People were randomized to receive either nine cycles of oral melphalan (M) plus prednisone (P) or MP plus bortezomib.<ref name="FDA PR 2008" /> People received M (9&nbsp;mg/m2 ) plus prednisone (60&nbsp;mg/m2 ) daily for four days every 6 weeks or the same MP schedule with bortezomib, 1.3&nbsp;mg/m2 iv on days 1, 8, 11, 22, 25, 29, and 32 of every 6 week cycle for 4 cycles then once weekly for 4 weeks for 5 cycles.<ref name="FDA PR 2008" /> Time- to- progression (TTP) was the primary efficacy endpoint.<ref name="FDA PR 2008" /> Overall survival (OS), progression-free survival (PFS), and response rate (RR) were secondary endpoints.<ref name="FDA PR 2008" /> Eligible people were age > 65 years.<ref name="FDA PR 2008" /> A total of 682 people were randomized: 338 to receive MP and 344 to the combination of bortezomib plus MP.<ref name="FDA PR 2008" /> Demographics and baseline disease characteristics were similar between the two groups.<ref name="FDA PR 2008" />
Gastro-intestinal (GI) effects and asthenia are the most common adverse events.<ref></ref>


The trial was stopped following a pre-specified interim analysis showing a statistically significant improvement in TTP with the addition of bortezomib to MP (median 20.7 months) compared with MP (median 15 months) .<ref name="FDA PR 2008" /> OS, PFS, and RR also were significantly superior for the bortezomib-MP combination.<ref name="FDA PR 2008" />
==Drug interactions==
Green tea extract ](EGCG), which had been expected to have a synergistic effect, was found by Encouse B. Golden, et al. to reduce the effectiveness of bortezomib.<ref>{{cite web | url=http://www.belfasttelegraph.co.uk/news/health/cancer-drug-benefits-could-be-negated-by-healthy-tea-treatment-14168666.html | title=Cancer drug benefits could be negated by healthy tea treatment | accessdate=2009-08-14 | publisher=Belfast Telegraph | date=3 February 2009}}</ref><ref>http://www.news-medical.net/?id=45529 "Green tea may counteract anticancer effects of cancer therapy, bortezomib (Velcade)"</ref><ref>http://www.ecancermedicalscience.com/news-insider-news.asp?itemId=414</ref><ref>{{cite journal | author=Golden EB, ''et al.'' | title=Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors | journal=Blood | year=2009 | pmid=19190249 | doi=10.1182/blood-2008-07-171389 | volume=113 | issue=23 | pages=5927–37}}</ref>


In August 2014, bortezomib was approved in the United States for the retreatment of adults with multiple myeloma<ref>{{Cite web|url = http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1957192&highlight=|archive-url = https://web.archive.org/web/20181101191919/http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1957192&highlight=|url-status = dead|archive-date = 1 November 2018|title = Millennium: The Takeda Oncology Company|date = 8 August 2014|website = .millennium.com}}</ref><ref name=pmid26629279 /> who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment.<ref name=pmid26629279>{{cite journal | vauthors = Raedler L | title = Velcade (Bortezomib) Receives 2 New FDA Indications: For Retreatment of Patients with Multiple Myeloma and for First-Line Treatment of Patients with Mantle-Cell Lymphoma | journal = American Health & Drug Benefits | volume = 8 | issue = Spec Feature | pages = 135–40 | date = March 2015 | pmid = 26629279 | pmc = 4665054 }}</ref>
==Therapeutic efficacy==
Two open-label, phase III trials established the efficacy of bortezomib 1.3&nbsp;mg/m<sup>2</sup> (with or without ]) administered by intravenous bolus on days 1,4,8, and 11 of a 21-day cycle for a maximum of eight cycles in heavily pretreated patients with relapsed/refractory multiple myeloma.<ref name="bortezo">Curran M, McKeage K..Drugs 2009;69(7):859-888.doi: 10.2165/00003495-200969070-00006.</ref> Another trial demonstrated the superiority of bortezomib 1.3&nbsp;mg/m<sup>2</sup> over a high-dose dexamethasone regimen.<ref name="bortezo"/>


In October 2014, bortezomib was approved in the United States for the treatment of treatment-naïve people with ].<ref name=pmid26629279 />
==Further improvement of anticancer potency==
Laboratory studies and ]s are investigating whether it might be possible to further increase the anticancer potency of bortezomib by combining it with novel types of other ] agents. For example, clinical trials have indicated that the addition of ], ], inhibitors of ] (]), or ] might be beneficial.<ref>{{cite journal | author=Anargyrou K ''et al.'' | title=Novel anti-myeloma agents and angiogenesis | journal=Leuk Lymphoma | volume=49| issue=4| pages=677–689| year=2008 | pmid=18398734 | doi=10.1080/10428190701861686}}</ref><ref>{{cite journal | author=Richardson PG ''et al.'' | title=Novel biological therapies for the treatment of multiple myeloma | journal=Best Pract Res Clin Haematol | volume=18| issue=4| pages=619–634| year=2005 | pmid=16026741 | doi=10.1016/j.beha.2005.01.010}}</ref> In laboratory studies, it was found that bortezomib killed ] cells more efficiently when combined, for example, with ]s,<ref>{{cite journal | author=Nawrocki ST ''et al.'' | title=Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells | journal=Cancer Res | volume=66| issue=7| pages=3773–3781| year=2006 | pmid=16585204 | doi=10.1158/0008-5472.CAN-05-2961}}</ref> ],<ref>{{cite journal | author=Nawrocki ST ''et al.'' | title=Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis | journal=Cancer Res | volume=65| issue=24| pages=11658–11666| year=2005 | pmid=16357177 | doi=10.1158/0008-5472.CAN-05-2370}}</ref> or ].<ref>{{cite journal | author=Kardosh A ''et al.'' | title=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 | journal=Cancer Res | volume=68| issue=3| pages=843–851| year=2008 | pmid=18245486 | doi=10.1158/0008-5472.CAN-07-5555}}</ref> However, the therapeutic efficacy of any of these latter combinations has not yet been confirmed in cancer patients.


A ready-to-use formulation of bortezomib was approved for medical use in the United States in September 2024.<ref name="Boruzu FDA label" /><ref>{{cite press release | title=Amneal and Shilpa Announce U.S. FDA Approval of Boruzu, the First Ready-to-Use Version of Bortezomib for subcutaneous administration | website=Business Wire | date=5 September 2024 | url=https://www.businesswire.com/news/home/20240905166831/en/ | access-date=5 October 2024}}</ref>
==References==

{{Reflist|2}}
== Society and culture ==
=== Economics ===
In the UK, ] initially recommended against Velcade in October 2006, due to its cost of about {{GBP|18,000}} per person, and because studies reviewed by NICE reported that it could only extend the life expectancy by an average of six months over standard treatment.<ref>{{cite web|url=http://news.bbc.co.uk/1/hi/health/6069386.stm | title=NHS watchdog rejects cancer drug | access-date=14 August 2009 | publisher=BBC News Online | date=20 October 2006 }}</ref> However, the company later proposed a performance-linked cost reduction for multiple myeloma,<ref>{{cite web |url=http://www.nice.org.uk/nicemedia/pdf/MyelomaDofHSummaryResponderScheme.pdf |title=Summary of Velcade Response Scheme |access-date=14 August 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090419091212/http://www.nice.org.uk/nicemedia/pdf/MyelomaDofHSummaryResponderScheme.pdf |archive-date=19 April 2009 }}</ref> and this was accepted.<ref>{{cite web | url=http://www.europharmatoday.com/2009/01/more-velcadestyle-risksharing-in-the-uk.html | archive-url=https://web.archive.org/web/20110710204841/http://www.europharmatoday.com/2009/01/more-velcadestyle-risksharing-in-the-uk.html | url-status=dead | archive-date=10 July 2011 | title=More Velcade-Style Risk-Sharing In The UK? | access-date=14 August 2009 | publisher=Euro Pharma Today | date=21 January 2009 }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | title = Bortezomib | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/bortezomib }}
* {{cite web | title=Bortezomib | website=National Cancer Institute | date=5 October 2006 | url=https://www.cancer.gov/about-cancer/treatment/drugs/bortezomib }}


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