| Indication |
For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies. |
| Pharmacodynamics |
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). |
| Absorption |
Not Available |
| Volume of distribution |
Not Available |
| Protein binding |
83% over the concentration range of 100-1000 ng/ml. |
| 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. |
| Route of elimination |
The pathways of elimination of bortezomib have not been characterized in humans. |
| 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. |
| Clearance |
- 102 L/h [patients with multiple myeloma following the first dose for doses of 1 mg/m2]
- 112 L/h [patients with multiple myeloma following the first dose for doses of 1.3 mg/m2]
- 15 – 32 L/h [patients with multiple myeloma following subsequent doses for doses of 1 and 1.3 mg/m2]
|
| 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. |
