Indications
Bortezomib is approved for use in adult patients diagnosed with multiple myeloma or mantle cell lymphoma. Its application in these conditions is based on its effectiveness in targeting specific cellular processes associated with these diseases.
Pharmacodynamics
Bortezomib functions by targeting the ubiquitin-proteasome pathway, a critical cellular mechanism responsible for maintaining protein concentrations within cells through protein degradation. Dysregulation of this pathway is commonly associated with pathological states, resulting in abnormal signaling and the development of malignant cells. Research has shown that chronic lymphocytic leukemia (CLL) cells from patients exhibit up to a threefold increase in chymotrypsin-like proteasome activity compared to normal lymphocytes. Bortezomib reversibly inhibits proteasomes, preventing them from mediating protein breakdown. It has demonstrated cytotoxic effects on various cancer cell types in vitro and has delayed tumor growth in animal models. Its inhibitory effect on the proteasome is dose-dependent, as evidenced by studies showing over 75% inhibition of proteasome activity in whole blood within an hour of administration.
Absorption
Following intravenous administration, the peak plasma concentrations (Cmax) of bortezomib were recorded at 57 ng/mL and 112 ng/mL for 1 mg/m^2 and 1.3 mg/m^2 doses, respectively. In a twice-weekly dosing schedule, Cmax values fluctuated between 67 to 106 ng/mL for the 1 mg/m^2 dose and 89 to 120 ng/mL for the 1.3 mg/m^2 dose. When bortezomib was administered subcutaneously to multiple myeloma patients, the Cmax was lower compared to intravenous administration; however, the total systemic drug exposure was comparable between the two methods. There is notable variability in plasma concentrations between different patients.
Metabolism
Bortezomib undergoes extensive metabolism primarily by cytochrome P450 enzymes, specifically CYP3A4, CYP2C19, and CYP1A2, with CYP2D6 and CYP2C9 playing minor roles. The major metabolic pathway involves oxidative deboronation, which results in the removal of boronic acid from the parent compound. The resulting metabolites are pharmacologically inactive, and over 30 distinct metabolites have been identified in both human and animal studies.
Mechanism of Action
Bortezomib functions as a reversible inhibitor of the 26S proteasome, a complex made up of a 20S core associated with a 19S regulatory unit. This structure plays a crucial role in the ubiquitin-proteasome pathway, a critical mechanism for intracellular protein degradation. Aberrations in this pathway, often present in various malignancies, can result in uncontrolled cell division and cancer progression. In mammalian cells, bortezomib specifically targets the proteasome's chymotryptic-like activity by binding to the β5-subunit's threonine hydroxyl group within the 20S core. Additionally, bortezomib inhibits the β1-subunit, responsible for the caspase-like activity, and the β1i-subunit, an alternative form expressed during cellular stress or inflammation. By interfering with the proteasome-mediated breakdown of proteins essential for cell apoptosis, bortezomib induces cell cycle arrest in the G2-M phase. Beyond proteasome inhibition, its anticancer efficacy is largely attributed to the suppression of the NF-κB signaling pathway, leading to reduced expression of anti-apoptotic genes and proteins. This suppression occurs as bortezomib inhibits the degradation of IκB, a protein inhibiting NF-κB. Furthermore, bortezomib has been shown to induce NOXA, a pro-apoptotic factor, selectively within cancer cells, suggesting another significant mechanism contributing to its anticancer effects.
