Bortezomib

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Bortezomib
Bortezomib.svg
Bortezomib-based-on-PDB-2F16-Mercury-3D-balls.png
Clinical data
Trade names Velcade, Chemobort, Bortecad, others
Other namesPS-341
AHFS/Drugs.com Monograph
MedlinePlus a607007
License data
Pregnancy
category
  • AU:C
Routes of
administration 		Subcutaneous, intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • US: ℞-only
  • EU:Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 83%
Metabolism Liver, CYP extensively involved
Elimination half-life 9 to 15 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.125.601 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H25BN4O4
Molar mass 384.24 g·mol−1
3D model (JSmol)
  • O=C(N[C@H](C(=O)N[C@H](B(O)O)CC(C)C)Cc1ccccc1)c2nccnc2
  • InChI=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 Yes check.svgY
  • Key:GXJABQQUPOEUTA-RDJZCZTQSA-N Yes check.svgY
   (verify)

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. [2] This includes multiple myeloma in those who have and have not previously received treatment. [3] It is generally used together with other medications. [3] It is given by injection. [2]

Contents

Common side effects include nausea, diarrhea, tiredness, low platelets, fever, numbness, low white blood cells, shortness of breath, rash and abdominal pain. [2] Other severe side effects include low blood pressure, tumour lysis syndrome, heart failure, and reversible posterior leukoencephalopathy syndrome. [2] [3] It is in the class of medications known as proteasome inhibitor. [2] It works by inhibiting proteasomes, cellular complexes that break down proteins. [3]

Bortezomib was approved for medical use in the United States in 2003 and in the European Union in 2004. [2] [3] It is on the World Health Organization's List of Essential Medicines. [4] It is available as a generic medication. [5]

Medical use

Two open-label trials established the efficacy of bortezomib (with or without dexamethasone) 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. [6] The phase III demonstrated the superiority of bortezomib over a high-dose dexamethasone regimen (e.g. median TTP 6.2 vs 3.5 months, and 1-year survival 80% vs 66%). [6] New studies show that bortezomib may potentially help recover from vincristine treatment in treating acute lymphoblastic leukemia, when replacing vincristine in the process. [7]

Bortezomib was also evaluated together with other drugs for the treatment of multiple myelomas in adults. It was seen that bortezomib plus lenalidomide plus dexamethasone as well as bortezomib plus melphalan and prednisone may result in a large increase in the progression-free survival. [8]

Adverse effects

Gastro-intestinal effects and asthenia are the most common adverse events. [9] Bortezomib is associated with peripheral neuropathy in 30% of people resulting in pain. This can be worse in people 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 people with advanced disease. Bortezomib is associated with a high rate of shingles, [10] although prophylactic acyclovir can reduce the risk of this. [11]

Ocular side effects such as chalazion or hordeolum (stye) may be more common in women and have led to discontinuation of treatment. [12] Acute interstitial nephritis has also been reported. [13]

Drug interactions

Polyphenols derived from green tea extract including epigallocatechin gallate (EGCG), which were expected to have a synergistic effect, instead were found to reduce the effectiveness of bortezomib in cell culture experiments. [14]

Pharmacology

Bortezomib bound to the core particle in a yeast 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 threonine residue whose activity is blocked by the presence of bortezomib. 2f16.png
Bortezomib bound to the core particle in a yeast 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 threonine residue whose activity is blocked by the presence of bortezomib.

Structure

The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid.

Mechanism

The boron atom in bortezomib is proposed to bind the catalytic site of the 26S proteasome [15] with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated 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. [16] 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 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). [17] [18] 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. [19]

The pharmacodynamics of bortezomib are determined by quantifying proteasome inhibition in peripheral blood mononuclear cells taken from people receiving the drug.

History

Bortezomib was originally made in 1995 at Myogenics. The drug (PS-341) was tested in a small Phase I clinical trial on people with multiple myeloma. It was brought to further clinical trials by Millennium Pharmaceuticals in October 1999. [20]

In May 2003, seven years after the initial synthesis, bortezomib (marketed as Velcade by Millennium Pharmaceuticals Inc.) 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. [21] [22] In 2008, bortezomib was approved in the United States for initial treatment of people with multiple myeloma. [23] 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. [23]

The 2008 approval was based on an international, multicenter, open label, active-control trial in previously untreated people with symptomatic multiple myeloma. [23] People were randomized to receive either nine cycles of oral melphalan (M) plus prednisone (P) or MP plus bortezomib. [23] People received M (9 mg/m2 ) plus prednisone (60 mg/m2 ) daily for four days every 6 weeks or the same MP schedule with bortezomib, 1.3 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. [23] Time- to- progression (TTP) was the primary efficacy endpoint. [23] Overall survival (OS), progression-free survival (PFS), and response rate (RR) were secondary endpoints. [23] Eligible people were age > 65 years. [23] A total of 682 people were randomized: 338 to receive MP and 344 to the combination of bortezomib plus MP. [23] Demographics and baseline disease characteristics were similar between the two groups. [23]

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) [HR: 0.54 (95% CI: 0.42, 0.70), p= 0.000002]. [23] OS, PFS, and RR also were significantly superior for the bortezomib-MP combination. [23]

In August 2014, bortezomib was approved in the United States for the retreatment of adults with multiple myeloma [24] [25] who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment. [25]

In October 2014, bortezomib was approved in the United States for the treatment of treatment-naïve people with mantle cell lymphoma (MCL). [25]

Society and culture

Economics

In the UK, NICE initially recommended against Velcade in October 2006, due to its cost of about £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. [26] However, the company later proposed a performance-linked cost reduction for multiple myeloma, [27] and this was accepted. [28]

See also

Related Research Articles

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Lenalidomide</span> Pair of enantiomers

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and generally with dexamethasone. It is taken by mouth.

Takeda Oncology is a biopharmaceutical company based in Cambridge, Massachusetts. It is a fully owned subsidiary of Takeda Pharmaceutical.

<span class="mw-page-title-main">Proteasome inhibitor</span>

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; three are approved for use in treating multiple myeloma.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

<span class="mw-page-title-main">Pixantrone</span> Chemical compound

Pixantrone is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.

Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone, for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma. It is also indicated for adult patients in combination with pomalidomide and dexamethasone, who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen. It is being developed by Bristol Myers Squibb and AbbVie.

<span class="mw-page-title-main">Plasma cell leukemia</span> Medical condition

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

<span class="mw-page-title-main">Panobinostat</span> Chemical compound

Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor.

<span class="mw-page-title-main">Pomalidomide</span> Chemical compound

Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">Daratumumab</span> Monoclonal antibody

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

<span class="mw-page-title-main">Filanesib</span> Chemical compound

Filanesib is a kinesin spindle protein (KIF11) inhibitor which has recently been proposed as a cancer treatment, specifically for multiple myeloma.

Polatuzumab vedotin, sold under the brand name Polivy, is a CD79b-directed antibody-drug conjugate medication used for the treatment of diffuse large B-cell lymphoma (cancer). It was developed by the Genentech subsidiary of Roche.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Melphalan flufenamide</span> Chemical compound

Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.

Bortezomib/dexamethasone is a combination drug against multiple myeloma. When bortezomib is used by the trade name Velcade, the combination is called Vel/Dex. Bortezomib is a proteasome inhibitor and dexamethasone is a corticosteroid.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Daratumumab/hyaluronidase, sold under the brand name Darzalex Faspro, is a fixed-dose combination medication for the treatment of adults with newly diagnosed or relapsed/refractory multiple myeloma. It is a combination of daratumumab and hyaluronidase. It is administered via subcutaneous injection.

References

  1. ↑ Baxter Healthcare Pty Ltd
  2. 1 2 3 4 5 6 "Bortezomib Monograph for Professionals". Drugs.com. Retrieved 13 October 2019.
  3. 1 2 3 4 5 "Velcade". European Medicines Agency (EMA). 17 September 2018. Retrieved 13 October 2019.
  4. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ↑ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  6. 1 2 Curran MP, McKeage K (2009). "Bortezomib: a review of its use in people with multiple myeloma". Drugs. 69 (7): 859–88. doi:10.2165/00003495-200969070-00006. PMID   19441872. Archived from the original on 8 October 2011. Retrieved 26 March 2010.
  7. ↑ Joshi J, Tanner L, Gilchrist L, Bostrom B (August 2019). "Switching to Bortezomib may Improve Recovery From Severe Vincristine Neuropathy in Pediatric Acute Lymphoblastic Leukemia". Journal of Pediatric Hematology/Oncology. 41 (6): 457–462. doi:10.1097/MPH.0000000000001529. PMID   31233464. S2CID   195357104.
  8. ↑ Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, et al. (Cochrane Haematology Group) (November 2019). "Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis". The Cochrane Database of Systematic Reviews. 2019 (11). doi:10.1002/14651858.CD013487. PMC   6876545 . PMID   31765002.
  9. ↑ "Highlights Of Prescribing Information" (PDF). Archived from the original (PDF) on 19 February 2009. Retrieved 19 December 2022.
  10. ↑ Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, et al. (June 2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". British Journal of Haematology. 129 (6): 755–62. doi: 10.1111/j.1365-2141.2005.05519.x . PMID   15953001. S2CID   34591121.
  11. ↑ Pour L, Adam Z, Buresova L, Krejci M, Krivanova A, Sandecka V, et al. (April 2009). "Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib". Clinical Lymphoma & Myeloma. 9 (2): 151–3. doi:10.3816/CLM.2009.n.036. PMID   19406726.
  12. ↑ Dennis M, Maoz A, Hughes D, Sanchorawala V, Sloan JM, Sarosiek S (March 2019). "Bortezomib ocular toxicities: Outcomes with ketotifen". American Journal of Hematology. 94 (3): E80–E82. doi: 10.1002/ajh.25382 . PMID   30575098.
  13. ↑ Cheungpasitporn W, Leung N, Rajkumar SV, Cornell LD, Sethi S, Angioi A, Fervenza FC (July 2015). "Bortezomib-induced acute interstitial nephritis". Nephrology, Dialysis, Transplantation. 30 (7): 1225–9. doi: 10.1093/ndt/gfv222 . PMID   26109684.
  14. ↑ Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, et al. (June 2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors". Blood. 113 (23): 5927–37. doi: 10.1182/blood-2008-07-171389 . PMID   19190249.
  15. ↑ Bonvini P, Zorzi E, Basso G, Rosolen A (April 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.
  16. ↑ Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, et al. (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". PLOS ONE. 8 (1): e53263. Bibcode:2013PLoSO...853263G. doi: 10.1371/journal.pone.0053263 . PMC   3538785 . PMID   23308178.
  17. ↑ Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, et al. (January 2011). "Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma". Cancer Chemotherapy and Pharmacology. 67 (1): 57–67. doi:10.1007/s00280-010-1283-3. PMC   3951913 . PMID   20306195.
  18. ↑ Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (December 2003). "The proteasome as a target for cancer therapy". Clinical Cancer Research. 9 (17): 6316–25. PMID   14695130.
  19. ↑ Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. (May 2011). "Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study". The Lancet. Oncology. 12 (5): 431–40. doi:10.1016/s1470-2045(11)70081-x. PMID   21507715.
  20. ↑ Larkin M (November 1999). "(In)famous trials brought to life". The Lancet. 354 (9193): 1915. doi:10.1016/s0140-6736(05)76886-0. ISSN   0140-6736. S2CID   53301933.
  21. ↑ Adams J, Kauffman M (2004). "Development of the proteasome inhibitor Velcade (Bortezomib)". Cancer Investigation. 22 (2): 304–11. doi:10.1081/CNV-120030218. PMID   15199612. S2CID   23644211.
  22. ↑ "Drug Approval Package: Velcade (Bortezomib) NDA #021602". U.S. Food and Drug Administration (FDA). 13 May 2003. Archived from the original on 5 December 2019. Retrieved 5 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  23. 1 2 3 4 5 6 7 8 9 10 11 12 "Velcade (bortezomib) is Approved for Initial Treatment of Patients with Multiple Myeloma" (Press release). U.S. Food and Drug Administration (FDA). 23 June 2008. Archived from the original on 1 December 2011. Retrieved 5 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  24. ↑ "Millennium: The Takeda Oncology Company". .millennium.com. 8 August 2014. Archived from the original on 1 November 2018.
  25. 1 2 3 Raedler L (March 2015). "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". American Health & Drug Benefits. 8 (Spec Feature): 135–40. PMC   4665054 . PMID   26629279.
  26. ↑ "NHS watchdog rejects cancer drug". BBC News Online. 20 October 2006. Retrieved 14 August 2009.
  27. ↑ "Summary of Velcade Response Scheme" (PDF). Archived from the original (PDF) on 19 April 2009. Retrieved 14 August 2009.
  28. ↑ "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 21 January 2009. Archived from the original on 10 July 2011. Retrieved 14 August 2009.
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