indication

For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

pharmacology

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).

toxicity

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.

biotransformation

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.

half life

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.

route of elimination

The pathways of elimination of bortezomib have not been characterized in humans.

drug interactions

Clopidogrel: Moderate CYP2C19 Inhibitors like bortezomib may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Avoid concurrent use of moderate CYP2C19 inhibitors with clopidogrel whenever possible. If such a combination must be used, monitor closely for evidence of reduced clinical response to clopidogrel.

Telithromycin: Telithromycin may reduce clearance of Bortezomib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Bortezomib if Telithromycin is initiated, discontinued or dose changed.

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Bortezomib. Consider alternate therapy or monitor for adverse/toxic effects of Bortezomib if Ticlopidine is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bortezomib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bortezomib if voriconazole is initiated, discontinued or dose changed.