Bortezomib

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Structural formula
Structure of bortezomib
General
Non-proprietary name Bortezomib
other names
  • (1 R ) -3-Methyl-1 - ({(2 S ) -3-phenyl-2 - [(2-pyrazinylcarbonyl) -amino] propanoyl} amino) butylboronic acid
  • PS-341 (development name)
Molecular formula C 19 H 25 BN 4 O 4
External identifiers / databases
CAS number 179324-69-7
EC number 605-854-3
ECHA InfoCard 100.125.601
PubChem 387447
DrugBank DB00188
Wikidata Q419319
Drug information
ATC code

L01 XX32

Drug class

Proteasome inhibitor

properties
Molar mass 384.24 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
09 - Dangerous for the environment 08 - Dangerous to health 06 - Toxic or very toxic

danger

H and P phrases H: 300-315-319-361-372-411
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Illustration of the binding of bortezomib to the nucleus of a proteasome. The bortezomib molecule in the center is colored according to the atomic type (carbon = cyan, nitrogen = blue, oxygen = red). It is surrounded by the local protein surface. The bruise is a threonine catalytic residue whose activity is blocked by bortezomib.

Bortezomib is a drug that has been approved for the treatment of multiple myeloma (plasmacytoma) . Bortezomib is the first in a new class, the proteasome - inhibitors , and as an injection preparation under the brand name Velcade in the US by Millennium Pharmaceuticals , a subsidiary of Takeda Pharmaceutical , and in Germany by Janssen-Cilag , a subsidiary of Johnson & Johnson marketed .

indication

In the EU, bortezomib has been approved as monotherapy since April 26, 2004 for the treatment of progressive multiple myeloma in patients who have had at least one previous therapy and who have undergone a bone marrow transplant or who are not suitable for a bone marrow transplant.

Since August 28, 2008, bortezomib in combination with melphalan and prednisone has been approved for the treatment of adult patients with previously untreated multiple myeloma who are not suitable for high-dose chemotherapy with bone marrow transplantation.

Bortezomib may also be used with other drugs to treat multiple myeloma, which has not been treated to date. In 2019, Piechotta et al. conducted a Cochrane review using a network meta-analysis of randomized controlled trials to compare the safety and effectiveness of multiple drug combinations for adults with newly-diagnosed and untreated multiple myeloma. Study participants had to be either older than 65 years or unsuitable for stem cell transplantation or high-dose therapy if they were between 18 and 65 years of age. Bortezomib was evaluated in the following combinations: bortezomib plus melphalan and prednisone & consecutively bortezomib plus lenalidomide plus dexamethasone . Whenever possible, these combinations were compared with melphalan plus prednisone, as this combination represents the median risk therapy. The results were as follows: The continued administration of bortezomib plus lenalidomide plus dexamethasone is likely to cause an increase in overall survival. Bortezomib plus melphalan and prednisone may cause a large increase in overall survival. Bortezomib plus melphalan and prednisone and the continued administration of bortezomib plus lenalidomide plus dexamethasone may cause a large increase in progression-free survival. Bortezomib plus melphalan and prednisone probably lead to a marked increase in the risk of polyneuropathy. The other medication was not compared here. The administration of bortezomib plus melphalan and prednisone is likely to cause an increase in serious adverse events. The other medication was not compared here. The continued administration of bortezomib plus lenalidomide plus dexamethasone caused a marked increase in patient discontinuation due to adverse events. Administration of bortezomib plus melphalan and prednisone likely caused a small increase in patient dropouts due to adverse events.

Bortezomib is being tested in clinical trials for other indications , such as other forms of haematological cancer and solid tumors . At the same time, the effectiveness against colon , lung , pancreas , breast , prostate and ovarian cancer and non-Hodgkin lymphomas is being tested. The substance is also used in the experimental treatment of anti-NMDA receptor encephalitis .

Application and dosage

The active ingredient is a freeze-dried powder in the form of a mannitol ester with the boronic acid group and must be dissolved in saline for injection purposes before administration . After preparation, the mannitol ester is in equilibrium with its hydrolysis product .

Bortezomib is administered intravenously or subcutaneously injected , the recommended dose is 1.3 mg per m 2 body surface . As a preventive measure, an anti-nausea agent can be administered and then flushed with saline solution (about 50 ml). It is recommended to check the blood count before each injection. For example, the platelet count , the white blood cell count and the hemoglobin value should be monitored. All three values ​​can decrease during therapy. The duration of treatment depends on the response of the disease; more than 8 cycles are usually not given. In the SUMMIT study, all patients who did not get disease progression and who did not experience serious side effects were treated with 8 cycles.

Mechanism of action

Proteasomes play an important role in the breakdown of proteins that regulate the cell cycle and thus cell growth . Bortezomib works by blocking the metabolic pathways of cancer cells , which are characterized by uncontrolled growth. If a proteasome blockage occurs, vital proteolysis processes are suppressed.

As a result, many signals in the cancer cell cancel each other out or are prevented. As a result, this leads to

  1. Inhibition of tumor growth
  2. Inhibition of angiogenesis (formation of new blood vessels to supply the tumor)
  3. Apoptosis of cancer cells (programmed cell death of the previously "immortal" cancer cells)
  4. Inhibition of interaction with connective tissue cells of the bone marrow.

Healthy cells are also affected by the therapy. However, it was found that these cells - in contrast to the cancer cells - regenerate if the treatment is interrupted for ten days after 4 injections on days 1, 4, 8 and 11. Obviously, cancer cells are particularly dependent on the function of the proteasomes and are therefore more sensitive to their inhibition than normal cells. The boron atom of bortezomib binds with a high affinity and selectivity as a ligand to the catalytic function of the 26S proteasome.

A highly specific and high affinity bond to the catalytic site of the 26S proteasome takes place via the boron , which is thereby inhibited.

Multiple myeloma (plasmacytoma) has so far been treated as treatable, but incurable. Bortezomib cannot be a cure either, but it is another alternative for those patients who have already failed at least one therapy.

metabolism

After a single intravenous dose, bortezomib plasma concentrations decrease biphasic. The decrease is characterized by a rapid distribution phase followed by a slower terminal elimination phase. In humans, the half-life is estimated to be 5 to 15 hours. In vitro , the cytochrome enzymes CYP3A4 and CYP2C19 were identified as the main metabolic enzymes . Only a small proportion of the non-metabolized parent substance was found in the urine, while no intact bortezomib was found in the bile or faeces .

Side effects

The most important side effect, which also essentially limits treatment with bortezomib, is peripheral neuropathy , a nerve disorder with pain and numbness, especially in the hands or feet. This side effect is difficult to influence therapeutically and can seriously affect the patient. According to the literature, up to 70% of patients are affected by this and the expression can be severe to very severe (Grade III-IV according to WHO) and lead to complete immobility of the patient. In these cases, the patient's quality of life is very significant and restricted for months. As a rule, the neuropathy regresses, but it can last for a very long time.

A study has shown that peripheral neuropathy occurred much less frequently when bortezomib was administered subcutaneously instead of intravenously, which is why this form of administration was approved by the EU Commission in September 2012 .

Other side effects, such as low blood cell counts (see above), nausea , diarrhea and fatigue (severe exhaustion) can occur.

Therapy costs

In the UK , bortezomib has a cost of treatment of £ 18,000  per patient per year. Although the drug in clinical trials extended the life span by several months, the British National Health Service (NHS) refused to cover costs in an initial draft. The National Institute for Health and Clinical Excellence (NICE) reviews the cost-effectiveness of new therapies for the NHS . A benchmark are the costs that have to be expended to gain a year of life in good quality of life ( quality-adjusted life years , QALY). A value of less than £ 30,000 per QALY is often required.

After several months of negotiations with the manufacturer, the NHS made the following promise in 2007: At the suggestion of the manufacturer, all patients for whom bortezomib is indicated should initially receive the drug for a maximum of four cycles. If remission of multiple myeloma is achieved during this time , therapy will be continued at the expense of the NHS. If remission is not achieved, therapy is discontinued and the NHS does not have to pay for the drugs used.

In effect, this means that the NHS only has to pay for therapy in those cases in which the drug has worked.

Trade names

Bortezomib is commercially available in Germany, Austria and Switzerland under the name Velcade.

literature

Web links

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . What is reproduced is a labeling of N, N ', N' '- ((2S, 2'S, 2''S) - (((1R, 1'R, 1''R) - (1, 3,5,2,4,6-trioxatriborinane-2,4,6-triyl) tris (3-methylbutane-1,1-diyl)) tris (azanediyl)) tris (1-oxo-3-phenylpropane-2, 1-diyl)) tris (pyrazine-2-carboxamide) Template: link text check / apostrophe in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on December 28, 2019.
  2. ↑ a b c d myelom.at: Velcade® - active ingredient bortezomib. ( Memento of August 8, 2007 in the Internet Archive ) Retrieved June 27, 2007.
  3. ↑ Medknowledge.de: Bortezomib (Velcade®) approved for multiple myeloma (plasmacytoma). ( Memento of September 5, 2007 in the Internet Archive ) Retrieved June 27, 2007.
  4. ↑ Velcade / Bortezomib (PDF; 89 kB). EMA (CHMP) EPAR Summary for the Public, accessed February 20, 2013.
  5. ↑ ema.europa.eu: Velcade® - active ingredient bortezomib. (PDF; 173 kB). Retrieved January 3, 2013.
  6. ↑ Vanessa Piechotta, Tina Jakob, Peter Langer, Ina Monsef, Christof Scheid: Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis . In: Cochrane Database of Systematic Reviews . November 25, 2019, doi : 10.1002 / 14651858.CD013487 ( wiley.com [accessed July 16, 2020]).
  7. ↑ a b ÖAZ current: Bortezomib. ( Memento of February 20, 2007 in the Internet Archive ) Retrieved June 27, 2007.
  8. ↑ a b New Drugs - Bortezomib. In: Pharmaceutical newspaper. Retrieved June 27, 2007.
  9. ↑ P. Bonvini, E. Zorzi, G. Basso, A. Rosolen: Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30 + anaplastic large cell lymphoma Leukemia 2007, Volume 21, Issue 4, pages 838-42, PMID 17268529 , doi: 10.1038 / sj.leu.2404528 .
  10. ^ PG Richardson, H. Briemberg, S. Jagannath, PY Wen, B. Barlogie, J. Berenson, S. Singhal, DS Siegel, D. Irwin, M. Schuster, G. Srkalovic, R. Alexanian, SV Rajkumar, S. . Limentani, M. Alsina, RZ Orlowski, K. Najarian, D. Esseltine, KC Anderson, AA Amato: Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib. In: Journal of Clinical Oncology . 24, 2006, pp. 3113-3120, PMID 16754936 .
  11. ↑ P. Moreau, H. Pylypenko, S. Grosicki, I. Karamanesht, X. Leleu, M. Grishunina, G. Rekhtman, Z. Masliak, T. Robak, A. Shubina, B. Arnulf, M. Kropff, J Cavet, DL Esseltine, H. Feng, S. Girgis, H. van de Velde, W. Deraedt, JL Harousseau: Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study . In: Lancet Oncol. 12 (5), 2011, pp. 431-440, doi: 10.1016 / S1470-2045 (11) 70081-X , PMID 21507715 .
  12. ↑ NICE: Cancer medication should only be paid for if it works. ( Memento of the original from March 17, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: aerzteblatt.de , June 5, 2007, accessed on May 7, 2010. @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de