Bortezomib SUN

Bortezomib SUN Uses, Dosage, Side Effects, Food Interaction and all others data.

Bortezomib SUN is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib SUN causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

Bortezomib SUN works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib SUN exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib SUN inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib.

Trade Name Bortezomib SUN
Availability Prescription only
Generic Bortezomib
Bortezomib Other Names Bortezomib
Related Drugs prednisone, methotrexate, dexamethasone, Revlimid, cyclophosphamide, Imbruvica, ibrutinib, Calquence, Velcade, Darzalex
Type
Formula C19H25BN4O4
Weight Average: 384.237
Monoisotopic: 384.196885774
Protein binding

Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins.

Groups Approved, Investigational
Therapeutic Class Targeted Cancer Therapy
Manufacturer
Available Country Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom
Last Updated: September 19, 2023 at 7:00 am
Bortezomib SUN
Bortezomib SUN

Uses

Bortezomib SUN is a proteasome inhibitor used for:

  • Treatment of patients with multiple myeloma
  • Treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy

Bortezomib SUN is also used to associated treatment for these conditions: Mantle Cell Lymphoma (MCL), Multiple Myeloma (MM)

How Bortezomib SUN works

The ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread.

Bortezomib SUN is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib SUN binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib.

Dosage

Bortezomib SUN dosage

The recommended dose of Bortezomib SUN is 1.3 mg/m2 administered as a 3 to 5 second bolus intravenous injection. Dose adjustment may be used to manage adverse events that occur during treatment

Side Effects

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Toxicity

The Lowest published toxic dose (TD Lo) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose.

The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies.

Precaution

Women should avoid becoming pregnant while being treated with Bortezomib SUN. Pregnant women should be apprised of the potential harm to the fetus

Peripheral neuropathy, including severe cases, may occur - manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with Bortezomib SUN only after careful risk-benefit assessment.

Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated.

Patients with risk factors for, or existing heart disease, should be closely monitored.

Acute diffuse infiltrative pulmonary disease has been reported.

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement.

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment.

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported.

Interaction

Ketoconazole: Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

Melphalan-Prednisone: Co-administration of melphalan prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant.

Omeprazole: Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib.

Cytochrome P450: Patients who are concomitantly receiving Bortezomib SUN and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy

Food Interaction

  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of bortezomib.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of bortezomib.
  • Limit foods and supplements high in flavonoids. Flavonoids may interfere with the therapeutic action of this drug. Foods high in flavonoids include green vegetables, fruits, and green tea.
  • Limit foods and supplements high in vitamin C. Vitamin C may interfere with the therapeutic action of this drug. Foods high in vitamin C include citrus fruits and beverages.

[Moderate] GENERALLY AVOID: Data from in vitro and animal (mice) studies suggest that green tea may antagonize the cytotoxic effects of bortezomib.

Polyphenols in green tea such as (-)-epigallocatechin gallate (EGCG) have been shown to block the proteasome inhibitory action of bortezomib in multiple myeloma and glioblastoma cancer cell lines.

The mechanism appears to involve a direct chemical reaction between the boronic acid moiety of bortezomib and the 1,2-benzenediol groups present in certain polyphenols leading to inactivation of bortezomib.

However, one group of investigators reported that no antagonism of bortezomib was observed in preclinical in vivo experiments where EGCG plasma concentrations are commensurate with dietary or supplemental intake.



MANAGEMENT: Until more data are available, it may be advisable to avoid or limit consumption of green tea and green tea products during treatment with bortezomib.

The interaction has not been demonstrated for other, non-boronic acid proteasome inhibitors.

Bortezomib SUN multivitamins interaction

[Moderate] GENERALLY AVOID: Preliminary data suggest that ascorbic acid may diminish the antitumor effects of bortezomib when taken simultaneously.

In vitro, ascorbic acid has been shown to inhibit several biologic activities of bortezomib, including induction of apoptosis and G2-M cell cycle arrest and inhibition of proteasome activity, presumably by forming a complex with bortezomib that is both inactive and has poor membrane permeability into cells.

A group of investigators showed that plasma from healthy volunteers taking 1 gram of vitamin C per day reduced bortezomib-induced multiple myeloma cell death in vitro.

Using a mouse model of human multiple myeloma, they also found that oral vitamin C (40 mg

The interaction has also been observed in an endometrial carcinoma cell line.

In contrast, no effect of ascorbic acid (at plasma concentrations commensurate with human supplemental intake) on bortezomib activity was found in immunocompromised mice bearing CWR22 human prostate xenograft tumors.

In light of the fact that vitamin C may protect normal cells from bortezomib toxicity, more studies are needed to further clarify the clinical significance of these findings.

Until more data are available, it may be advisable to avoid taking supplements containing ascorbic acid during bortezomib therapy, or at least on bortezomib treatment days.

Volume of Distribution

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m2 or 1.3 mg/m2. Bortezomib SUN distributes into nearly all tissues, except for the adipose and brain tissue.

Elimination Route

Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses, the mean Cmax of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the Cmax ranged from 67 to 106 ng/mL at the dose of 1 mg/m2 and 89 to 120 ng/mL for the 1.3 mg/m2 dose. In patients with multiple myeloma, the Cmax of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations.

Half Life

The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m2 dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m2 bortezomib.

Clearance

Following the administration of a first dose of 1 mg/m2 and 1.3 mg/m2, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m2, respectively.

Elimination Route

Bortezomib SUN is eliminated by both renal and hepatic routes.

Pregnancy & Breastfeeding use

Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib SUN. Bortezomib SUN administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post implantation loss and a decreased number of live fetuses.

Contraindication

Bortezomib SUN is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol

Storage Condition

Unopened vials may be stored at controlled room temperature 25º C

Innovators Monograph

You find simplified version here Bortezomib SUN

Bortezomib SUN contains Bortezomib see full prescribing information from innovator Bortezomib SUN Monograph, Bortezomib SUN MSDS, Bortezomib SUN FDA label

*** Taking medicines without doctor's advice can cause long-term problems.
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