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Bortezomib, sold under the brand name Velcade among others, is an
anti-cancer medication Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
used to treat
multiple myeloma 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, anem ...
and
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection. Common side effects include nausea, diarrhea, tiredness, low platelets, fever, numbness,
low white blood cells Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of in ...
, shortness of breath, rash and abdominal pain. Other severe side effects include low blood pressure,
tumour lysis syndrome Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off ( lysed) from the treatment, releasing their contents into the bloo ...
, heart failure, and reversible posterior leukoencephalopathy syndrome. It is in the class of medications known as
proteasome inhibitor 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; and three are approved for use in treating multiple myeloma. Mechanism Multip ...
. It works by inhibiting
proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by wh ...
s, cellular complexes that break down proteins. Bortezomib was approved for medical use in the United States in 2003 and in the European Union in 2004. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.


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. 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%). New studies show that bortezomib may potentially help recover from vincristine treatment in treating acute lymphoblastic leukemia, when replacing vincristine in the process. Bortezomib was also evaluated together with other drugs for the treatment of multiple myelomas in adults. It was seen that bortezomib plus
lenalidomide Lenalidomide, sold under the trade 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 gene ...
plus dexamethasone as well as bortezomib plus
melphalan Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is taken by mouth or by injection into a vein. Common side effects includ ...
and
prednisone Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adre ...
may result in a large increase in the progression-free survival.


Adverse effects

Gastro-intestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
effects and
asthenia Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...
are the most common adverse events. Bortezomib is associated with
peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
in 30% of people resulting in pain. This can be worse in people with pre-existing
neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
. In addition,
myelosuppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity ( leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting ( ...
causing
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
and
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients and ...
can also occur and be dose-limiting. However, these
side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...
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, although
prophylactic Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
acyclovir Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following tran ...
can reduce the risk of this. Ocular side effects such as chalazion or hordeolum (stye) may be more common in women and have led to discontinuation of treatment. Acute interstitial nephritis has also been reported.


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.


Pharmacology


Structure

The drug is an N-protected
dipeptide A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiological ...
and can be written as Pyz-Phe-boroLeu, which stands for
pyrazinoic acid Pyrazinoic acid is a pyrazinamide metabolite. Possible role in tuberculosis treatment Pyrazinamid is currently used as a treatment for tuberculosis. Mycobacterium tuberculosis converts pyrazinamid into pyrazinoic acid. The use of pyrazinoic acid ...
, phenylalanine and
Leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- c ...
with a
boronic acid A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, memb ...
instead of a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
.


Mechanism

The
boron Boron is a chemical element with the symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the ''boron group'' it has th ...
atom in bortezomib binds the catalytic site of the
26S proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...
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. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome. 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). 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. 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 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, anem ...
. It was brought to further clinical trials by
Millennium Pharmaceuticals Takeda Oncology (originally Millennium Pharmaceuticals) is a biopharmaceutical company based in Cambridge, Massachusetts. It is a fully owned subsidiary of Takeda Pharmaceutical. Takeda Oncology's research, development and commercialization acti ...
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. In 2008, bortezomib was approved in the United States for initial treatment of people with multiple myeloma. 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. The 2008 approval was based on an international, multicenter, open label, active-control trial in previously untreated people with symptomatic multiple myeloma. People were randomized to receive either nine cycles of oral melphalan (M) plus prednisone (P) or MP plus bortezomib. 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. Time- to- progression (TTP) was the primary efficacy endpoint. Overall survival (OS), progression-free survival (PFS), and response rate (RR) were secondary endpoints. Eligible people were age > 65 years. A total of 682 people were randomized: 338 to receive MP and 344 to the combination of bortezomib plus MP. Demographics and baseline disease characteristics were similar between the two groups. 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) R: 0.54 (95% CI: 0.42, 0.70), p= 0.000002 OS, PFS, and RR also were significantly superior for the bortezomib-MP combination. In August 2014, bortezomib was approved in the United States for the retreatment of adults with multiple myeloma who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment. In October 2014, bortezomib was approved in the United States for the treatment of treatment-naïve people with
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
(MCL).


Society and culture


Economics

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


See also

*
Ixazomib Ixazomib (trade name Ninlaro) 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. Common side effects include diarrhea, constipation a ...
, a proteasome inhibitor that is given by mouth * Peter Elliott (pharmacologist)


References


External links

* * * {{Portal bar, Medicine Boronic acids Carboxamides Johnson & Johnson brands Janssen Pharmaceutica Orphan drugs Propionamides Proteasome inhibitors Pyrazines Takeda Pharmaceutical Company brands World Health Organization essential medicines Wikipedia medicine articles ready to translate