Brands, Medical Use, Clinical Data
- Antineoplastic Agents
- Protease Inhibitors
- Powder for intravenous injection solution (each single dose vial contains 3.5 mg of bortezomib)
Brands / Synonyms
For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.
Bortezomib is a drug that inhibits the mammalian 26S proteasome. 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 causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Tumor cells, that is, rapidly dividing cells, appear to be more sensitive to proteasome inhibition.
Mechanism of Action
Bortezomib 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 active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).
Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration.
Biotrnasformation / Drug Metabolism
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2, while bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites which are inactive as 26S proteasome inhibitors.
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
No formal drug interaction studies have been conducted with VELCADE.
In vitro studies with human liver microsomes indicate that bortezomib is primarily a substrate for
cytochrome P450 3A4, 2C19, and 1A2. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or
inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy .
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral
hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their
blood glucose levels and adjustment of the dose of their antidiabetic medication.
Drug Laboratory Test Interactions