Bortezomib

Bortezomib is an antineoplastic agent belonging to the pharmacological class of proteasome inhibitors.

The FDA approved Bortezomib for treating multiple myeloma and mantle cell lymphoma.

Bortezomib is administered intravenously or subcutaneously for direct bloodstream entry, facilitating broad distribution across peripheral tissues. Metabolism primarily occurs in the liver through various cytochrome P450 enzymes, with elimination half-life varying based on dosing, ranging from 9 to 193 hours.

The most common side effects of Bortezomib include fatigue, nausea, vomiting, and loss of appetite.

Bortezomib is available in injectable lyophilized powder.

The molecule is available in India, Canada, Japan, China, the United States, the United Kingdom, and European Union member states like Austria, Germany, France, Brazil, Portugal, Romania, Spain and many more.

Bortezomib is an antineoplastic agent belonging to the pharmacological class of proteasome inhibitors.

Bortezomib inhibits the 26S proteasome's chymotrypsin-like activity in mammalian cells. The 26S proteasome, a sizable protein complex, breaks down ubiquitinated proteins. The ubiquitin-proteasome pathway is crucial in controlling the intracellular concentration of particular proteins to keep cells in homeostasis. This targeted proteolysis is stopped by inhibition of the 26S proteasome, which can impact several signalling pathways in the cell. Cell death may result from this interference with regular homeostatic processes. In vitro experiments have shown that Bortezomib is cytotoxic to several types of cancer cells. Bortezomib delays the growth of tumours in vivo in nonclinical tumour models, such as multiple myeloma.

The peak plasma level of Bortezomib reaches 509 ng/mL, indicating the concentration in the bloodstream after administration.

Bortezomib is available in injectable lyophilized powder.

Injectable lyophilized powder: To use Bortezomib injectable lyophilized powder, reconstitute the vial with the provided diluent, resulting in a solution for parenteral administration as applicable.

As the physician recommends, take the medication twice weekly for 2 weeks; it can be taken with or without food as directed.

Bortezomib for injection is indicated for treating the following conditions:

Parenterally: Administer Bortezomib lyophilized powder exclusively via IV or SC routes, avoiding other administration routes. Reconstitute the lyophilized powder with an appropriate diluent, following aseptic techniques. The recommended dosage involves twice-weekly administration for two weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12-21) within a 21-day cycle. Deliver as a bolus over 3-5 seconds for IV administration through a dedicated IV line. For SC injection, administered in the thigh or abdomen, rotating injection sites with each dose. Monitor hydration to prevent dehydration; maintain adequate fluid intake during treatment.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Bortezomib is available as an injectable powder.

1.3 mg/m²/dose IV twice weekly for 2 weeks (days 1, 4, 8, 11), followed by a 10-day rest period (days 12 - 21) for six three-week cycles; may extend for eight cycles if the response is observed at cycle 6.

Administer doxorubicin 50 mg/m² IV, cyclophosphamide 750 mg/m² IV, rituximab 375 mg/m² IV, and prednisone 100 mg/m² IV on days 1 to 5.

1.3 mg/m²/dose IV or SC twice weekly for 2 weeks (days 1, 4, 8, 11) with a 10-day rest period in between (days 12 to 21) in case of relapse

Beyond eight cycles of therapy: Provide a regular schedule.

Include prednisone and melphalan into 6-week treatment cycles for a total of nine cycles of administration.

Cycles 1-4 (twice weekly): Days 1, 4, 8, 11, 22, 25, 29, and 32 at 1.3 mg/m² IV/SC

Cycles 5–9: 1.3 mg/m² IV/SC on Days 1, 8, 22, and 29 (once every week).

twice weekly for two weeks (Days 1, 4, 8, and 11) at a dose of 1.3 mg/m²/IV/SC, with a 10-day rest period in between (Days 12–21)

Beyond eight cycles of therapy: Typical schedule: once a week for four weeks (Days 1, 8, 15, and 22) and then a thirteen-day break (Days 23 to 35)

At the last tolerable dose, treatment can be started.

Administer twice a week for two weeks (days 1, 4, 8, and 11). After that, take ten days off (days 12 to 21).

There aren't specific dietary restrictions. Maintain a healthy, balanced diet by incorporating leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs. Smoking and alcohol consumption should be avoided. Steer clear of fast food, fried items, processed meats, refined carbohydrates, and added sugars for optimal well-being.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Bortezomib can be categorized as:

Cardiovascular: Complete atrioventricular block, tamponade of the heart

GI: Acute pancreatitis, hepatitis, and ischemic colitis

CNS: Herpes meningoencephalitis, demyelinating polyneuropathy, PRES (previously RPLS), encephalopathy, acute diffuse infiltrative pulmonary disease, dysautonomia, progressive multifocal leukoencephalopathy (PML), and Guillain-Barre syndrome

Hematologic: Disseminated intravascular coagulation

Disease of the lungs: Acute diffuse infiltrative pulmonary disease.

Skin: acute febrile neutrophilic dermatosis (Sweet's syndrome), toxic epidermal necrolysis, Stevens-Johnson syndrome;

Sensory: ophthalmic herpes, chalazion/blepharitis, blindness, bilateral deafness, and optic neuropathy

The clinically relevant drug interactions of Bortezomib are briefly summarized here.

The common side effects of Bortezomib include:

dizziness

lightheadedness

nausea

vomiting

loss of appetite

diarrhoea

constipation

tiredness

weakness

pain or redness at the site where injection was administered.

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Drug-associated risks in pregnant women have not been studied; therapy, when administered to a pregnant woman, can harm the fetus due to its mechanism of action and findings in animals; treatment caused embryo-fetal lethality in rabbits at doses much lower than the clinical dose; Explain the danger to the fetus to expectant mothers.

Before starting treatment, make sure all females who are capable of bearing children are pregnant.

For women, use effective contraception during treatment and for a whole year following the last dosage.

Males: During treatment and for four months following the last dosage, males who have female partners who are capable of reproducing should use effective contraception.

The drug's mechanism of action and animal findings suggest that it may affect male or female fertility.

No information is available regarding Bortezomib, its metabolites in human milk, its effects on breastfed infants, or milk production.

Numerous medications are excreted in human milk, and it is unknown whether therapy may cause significant side effects in breastfed infants.

Inform nursing mothers not to breastfeed for two months after and during treatment.

As per the FDA, Bortezomib's use in pediatric patients has not been established.

The safety and efficacy of Bortezomib in the geriatric population have been studied. Caution is advised due to potential heightened sensitivity to medication in elderly individuals, necessitating close monitoring for adverse effects and adjusting doses based on individual health conditions.

Moderate to severe kidney impairment (creatinine clearance < 50 mL/min): Reduce the recommended starting dose of Bortezomib. Adjustments should be made based on the degree of impairment, ranging from a 25% reduction for moderate impairment to a 50% reduction for severe impairment.

Moderate-to-severe (Bilirubin >1.5x ULN): In the first cycle, lower to 0.7 mg/m²; depending on tolerability, consider increasing to 1 mg/m² or lowering the dose even further to 0.5 mg/m² in subsequent cycles.

The physician should be vigilant about the knowledge pertaining to the detection and management of Bortezomib overdosage.

Overconsumption of Bortezomib may lead to acute onset of symptomatic hypotension and thrombocytopenia.

There is no specific antidote or treatment for overdosage of Bortezomib. Once overdosage is detected, the administration of the drug should be promptly stopped or discontinued.

In the event of Bortezomib overdosage, provide supportive care and promptly initiate appropriate medical interventions to manage symptoms and prevent complications. Monitor vital signs, cardiac function, and electrolyte levels closely. Assess hepatic function due to Bortezomib's liver metabolism. Continuously observe for signs of neurotoxicity, emphasizing the absence of a specific antidote. Focus on addressing symptoms, including respiratory and cardiac functions. Emphasize the vital need to receive prompt medical attention to minimize any potential side effects that may result from a Bortezomib overdose.

Targeted by Bortezomib, the ubiquitin-proteasome pathway is a crucial molecular pathway that controls intracellular protein concentrations and stimulates protein degradation. Pathological conditions frequently result in dysregulation of the ubiquitin-proteasome pathway, which can cause aberrant pathway signalling and the development of malignant cells. Chymotrypsin-like proteasome activity was three times higher in patient-derived chronic lymphocytic leukaemia (CLL) cells compared to normal lymphocytes in one study. Bortezomib reversibly inhibits the proteasome, thereby preventing proteasome-mediated proteolysis. In vitro, bortezomib exhibits cytotoxicity against diverse cancer cell types and inhibits the growth of tumours in vivo in nonclinical tumour models. The activity of the proteasome is dose-dependently inhibited by boratezamib. In one pharmacodynamic study, within an hour of bortezomib dosing, whole blood samples showed more than 75% proteasome inhibition.