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Bortezomib

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Bortezomib

Bortezomib
Systematic (IUPAC) name
[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
Clinical data
Trade names Velcade
AHFS/Drugs.com
MedlinePlus
Licence data EMA:, US FDA:
Pregnancy cat.
Legal status
  • Prescription only
Routes Intravenous
Pharmacokinetic data
Protein binding 83%
Metabolism Hepatic, CYP extensively involved
Half-life 9 to 15 hours
Identifiers
CAS number  YesY
ATC code L01
PubChem
DrugBank
ChemSpider  YesY
UNII  YesY
ChEMBL  YesY
Chemical data
Formula C19H25BN4O4 
Mol. mass 384.237 g/mol
 YesY   

Bortezomib (BAN, INN and USAN. Originally codenamed PS-341; marketed as Velcade by Millennium Pharmaceuticals and Cytomib by Venus Remedies) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma.[1][2] In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Origin and development

Bortezomib was originally synthesized in 1995 at Myogenics. The drug (PS-341) was tested in a small Phase I clinical trial on patients with Multiple Myeloma. It was brought to further clinical trials by Millennium Pharmaceuticals in October 1999.

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.[3] Bortezomib is approved for initial treatment of patients with Multiple Myeloma by the U.S. FDA in 2008.[4]

Later in August 2014, this Administration approved Velcade for the retreatment of adult patients with Multiple Myeloma[5] who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment.

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.

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. 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.

Mechanism

The boron atom in bortezomib binds the catalytic site of the 26S proteasome[6] with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated 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. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome.[7] 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

Bortezomib is rapidly cleared following intravenous administration.[8] 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.[9]

The company proposed a cost reduction for multiple myeloma,[10] and this was taken up in the UK.[11]

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,[12] although prophylactic acyclovir can reduce the risk of this.[13]

Gastro-intestinal (GI) effects and asthenia are the most common adverse events.[14]

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.[15]

Therapeutic efficacy

Two open-label, phase II trials (SUMMIT and CREST) established the efficacy of bortezomib 1.3 mg/m2 (with or without dexamethasone) 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.[16] The phase III APEX trial demonstrated the superiority of bortezomib 1.3 mg/m2 over a high-dose dexamethasone regimen (e.g. median TTP 6.2 vs 3.5 months, and 1-year survival 80% vs 66%).[16]

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. ^ House, Douglas W. (2014-10-09). "FDA clears Velcade label expansion".  
  3. ^ Adams J, Kauffman M (2004). "Development of the Proteasome Inhibitor Velcade (Bortezomib)". Cancer Invest 22 (2): 304–11.  
  4. ^ "U.S. Department of Health and Human Services". fda.gov. June 23, 2008. 
  5. ^ "Millenium: The Takeda Oncology Company". .millennium.com. 2014-08-08. 
  6. ^ 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.  
  7. ^ Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". PLoS One 8 (8): e53263.  
  8. ^ 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.  
  9. ^ "NHS watchdog rejects cancer drug". BBC News UK. 2006-10-20. Retrieved 2009-08-14. 
  10. ^ "Summary of VELCADE Response Scheme". Retrieved 2009-08-14. 
  11. ^ "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 2009-01-21. Retrieved 2009-08-14. 
  12. ^ 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.  
  13. ^ Pour L., Adam Z., Buresova L., et al. (2009). "Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib". Clinical Lymphoma & Myeloma 9 (2): 151–3.  
  14. ^ Highlights Of Prescribing Information
  15. ^ Golden, EB; Lam, PY; Kardosh, A; Gaffney, KJ; Cadenas, E; Louie, SG; Petasis, NA; Chen, TC; Schönthal, AH (4 June 2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.". Blood 113 (23): 5927–37.  
  16. ^ a b Curran M, McKeage K. (2009). "Bortezomib: A Review of its Use in Patients with Multiple Myeloma". Drugs 69 (7): 859–888.   doi:10.2165/00003495-200969070-00006.

External links

  • [1]
  • 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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