Bortezomib

What is Bortezomib?

Bortezomib is a chemotherapy drug used to treat multiple myeloma and some types of lymphoma.

It works by interfering with the way cells break down proteins, causing cancer cells to accumulate damaged proteins and die.

It's given either as an injection under the skin or into a vein.

How does it work?

Bortezomib blocks proteasomes, which are parts of a cell responsible for breaking down unneeded or damaged proteins. When this system is blocked, cancer cells, which are more sensitive to this stress than normal cells, die off.

Pharmacodynamics (PD)

Mechanism of Action:
Bortezomib reversibly inhibits the 26S proteasome, a protein complex responsible for degrading ubiquitin-tagged proteins. This inhibition causes protein accumulation, oxidative stress, and apoptotic signaling in cells.

Selective Action on Cancer Cells:
Cancer cells rely heavily on proteasomes to manage misfolded proteins due to their rapid division. Blocking the proteasome disrupts their homeostasis more severely than in normal cells, leading to cell death.

Dose-Response:
The therapeutic effect is dose-dependent, with a plateau at higher doses due to saturation of proteasome inhibition. The drug spares non-cancerous cells to a degree, reducing off-target effects.

Key Outcomes:

Induction of apoptosis in cancer cells.

Suppression of angiogenesis (formation of blood vessels supporting tumors).

Altered cytokine signaling in the tumor microenvironment.

Pharmacokinetics (PK)

Absorption:
Bortezomib can be administered intravenously (IV) or subcutaneously (SC). Bioavailability is near 100% with IV administration. SC injection achieves similar exposure levels with reduced side effects like neuropathy.

Distribution:
Bortezomib binds extensively to plasma proteins, primarily albumin (>80%). It distributes widely in tissues, with a high volume of distribution (~500-1,000 L). This distribution facilitates action in bone marrow where myeloma cells are located.

Metabolism:
The drug is primarily metabolized by the liver via the cytochrome P450 system, especially CYP3A4, CYP2C19, and CYP1A2. Metabolites are less active and eventually excreted.

Elimination:
Clearance is biphasic. The half-life of Bortezomib is short initially (~5-15 hours), but elimination slows in the later phase. It's predominantly cleared through hepatic metabolism, with minimal renal clearance.