Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
Antineoplastic Agents Antineoplastic and Immunomodulating Agents Cytochrome P-450 CYP1A2 Inhibitors Cytochrome P-450 CYP2C9 Inhibitors Cytochrome P-450 CYP1A2 Inducers Cytochrome P-450 CYP2C8 Inhibitors Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C8 Inducers CYP2D6 Inducers CYP2D6 Inducers (strong) CYP3A4 Inhibitors
Bortezomib 2 MG
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.
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).
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.
The pathways of elimination of bortezomib have not been characterized in humans.
The mean elimination half-life of bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies.
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.
Citrus fruits - Patients should avoid taking extra vitamin C (ascorbic acid) supplements and vitamin C-containing multi-vitamins during their bortezomib therapy. Ascorbic Acid may diminish the therapeutic effect of Bortezomib. Green Tea - Green Tea may diminish the antineoplastic effect of Bortezomib. Avoid concurrent use of green tea extract and other green tea products during treatment with bortezomib.
Anemia, low white blood cell count, and low platelet count. Blurred eyesight. Use care when driving or doing other tasks that call for clear eyesight. Feeling dizzy. Rise slowly over a few minutes when sitting or lying down. Be careful climbing. Upset stomach or throwing up. Many small meals, good mouth care, sucking hard, sugar-free candy, or chewing sugar-free gum may help. Hard stools (constipation). Drinking more liquids, working out, or adding fiber to your diet may help. Talk with your doctor about a stool softener or laxative. Loose stools (diarrhea). Low blood pressure. Anemia. Viral infection. Fever. Feeling tired or weak. Numbness and tingling. Muscle pain. Headache.