Bortezomib

Bortezomib for Injection is an antineoplastic medicine given as an intravenous (IV) or subcutaneous injection. It reversibly blocks the chymotrypsin-like activity of the 26S proteasome in mammalian cells. This proteasome is a large protein complex that breaks down ubiquitinated proteins. The ubiquitin-proteasome pathway has an essential role in regulating the intracellular concentration of specific proteins, and that keeps the cell in balance (homeostasis). When Bortezomib inhibits the 26S proteasome, this targeted breakdown of proteins is stopped, which can affect multiple signaling cascades within the cell. Normal homeostatic mechanisms are disrupted, and this can lead to cell death. Experiments have shown that Bortezomib is cytotoxic to many types of cancer cells in vitro. In nonclinical tumor models, including multiple myeloma, it delays tumor growth in vivo.

Distribution:

In patients with multiple myeloma, the distribution volume of Bortezomib as a single agent was not assessed at the recommended dose. Binding to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.

Metabolism:

Bortezomib is mainly metabolised by oxidation through cytochrome P450 enzymes 3A4, 2C19 and 1A2. CYP 2D6 and 2C9 enzymes play only a minor part. The major pathway is deboronation, which forms 2 deboronated metabolites, and these then undergo hydroxylation to several metabolites. Deboronated Bortezomib metabolites are inactive as 26S proteasome inhibitors.

Elimination:

In patients with advanced malignancies, the mean elimination half-life of Bortezomib after the first dose ranged from 9 to 15 hours at doses from 1.45 to 2.00 mg/m2. How Bortezomib leaves the body has not been characterized in humans.