ONBORT 2,5 mg/1,0 ml

Indications

• Multiple myeloma
• Mantle cell lymphoma

Dosage

Children: Consult the BNF for Children for specific dosing recommendations.

Adults: Consult product literature or local protocols for specific dosing recommendations.

Mechanism of action

Bortezomib is a reversible inhibitor of the 26S proteasome, which is a multimeric protease complex responsible for degrading ubiquitin-tagged proteins. This inhibition prevents the breakdown of pro-apoptotic factors and cell cycle regulators, leading to increased apoptosis and cell cycle arrest in cancer cells. Bortezomib binds specifically to the active site of the β5-subunit of the proteasome, and also affects the β1 and β1i subunits, which contributes to its anticancer activity.

Pharmacodynamics

Bortezomib targets the ubiquitin-proteasome pathway, which is often dysregulated in cancer. By inhibiting proteasome activity, bortezomib increases the intracellular levels of pro-apoptotic proteins and disrupts signaling pathways that promote cancer cell survival. Studies have shown that bortezomib exerts cytotoxic effects on various cancer cell types in vitro and significantly delays tumor growth in vivo. Its effects on proteasome activity can be observed within one hour of administration, with over 75% inhibition noted in whole blood samples.

Pharmacokinetics

Bortezomib is administered either intravenously or subcutaneously. It has a plasma half-life of approximately 40 hours, and its pharmacokinetics can be influenced by various factors including the method of administration and patient-specific characteristics. Dose adjustments may be necessary in cases of hepatic impairment. The drug is primarily eliminated through proteolytic degradation rather than hepatic metabolism, which is important for patients with liver dysfunction.

Contra-indications

• Acute diffuse infiltrative pulmonary disease
• Herpes zoster reactivation
• JC virus disease
• Progressive multifocal leukoencephalopathy
• Pericardial disease

Adverse effects

• Anaemia
• Anxiety
• Appetite changes
• Asthenia
• Chills
• Constipation
• Cough
• Decreased leukocytes
• Diabetes mellitus
• Diarrhoea
• Dizziness
• Dysphagia
• Dyspnoea
• Electrolyte imbalance
• Encephalopathy
• Eye inflammation
• Fatigue
• Nausea
• Neuropathy
• Vomiting

Interactions

• Mitotane: Severe (decreases exposure)
• Cobicistat: Unknown (increases exposure)
• Idelalisib: Unknown (increases exposure)
• Clarithromycin: Unknown (increases exposure)
• Rifampicin: Unknown (decreases exposure)

Precautions

• Caution in patients with amyloidosis
• Caution in patients with cardiovascular disease
• Consider antiviral prophylaxis for herpes zoster infection
• Monitor for toxicity in patients with moderate to severe hepatic impairment
• Effective contraception is advised during and for 3 months after treatment

Pregnancy

Toxicity in animal studies; use with caution.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a refrigerator (2-8°C). Protect from light.

Formulations

• Injection for intravenous or subcutaneous administration

Mechanism of action

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 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 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. Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent. The drug reversibly inhibits the 26S proteasome, 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 by bortezomib prevents targeted proteolysis and causes disruption of normal homeostatic mechanisms, which can lead to cell death. In vitro studies indicate that bortezomib is cytotoxic to a variety of cancer cell types. Bortezomib has been shown to cause a delay in tumor growth in vivo in tumor models, including multiple myeloma. ... The mechanisms underlying /bortezomib/ cancer cell toxicity are complex. A growing body of evidence suggests proteasome inhibition-dependent regulation of the BCL-2 family is a critical requirement. In particular, the stabilization of BH3-only proteins BIK, NOXA and BIM, appear to be essential for effecting BAX- and BAK-dependent cell death. ... Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. ... Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. /Investigators/ have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective

Pharmacodynamics

Bortezomib 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 exerts a cytotoxic effect on various cancer cell types _in vitro_ and delays tumour growth _in vivo_ in nonclinical tumour models. Bortezomib 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.