Biomib Mechanism of Action

Pharmacologic Classification: Antineoplastic.
Pharmacology: Mechanism of Action: Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent. The drug potently, reversibly, and specifically inhibits the proteolytic activity of mammalian 26S proteasome, a large protein complex that degrades ubiquitinated proteins. Bortezomib is highly selective for the proteasome; it is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The ubiquitin-proteasome pathway has a vital role in regulating the intracellular concentration of specific proteins, consequently maintaining homeostasis within cells.
The bortezomib-mediated proteasome inhibition impedes targeted proteolysis, affecting multiple intracellular signaling cascades. The disruption of normal homeostatic mechanisms can ultimately lead to cancer cell death.
Proteasome inhibition by bortezomib affects the cancer cells in various ways, including, but not limited to, the alteration of regulatory proteins responsible for the cell cycle progression and the activation of nuclear factor kappa B (NF-κB), a transcription factor. Inhibition of the proteasome leads to cell cycle arrest and apoptosis, while NF-κB activation is necessary for many phases of tumorigenesis, such as cell growth and survival, angiogenesis, cell-cell interactions, and metastasis.
In vitro studies demonstrated that bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment. It has also been shown that bortezomib is cytotoxic to different types of cancer cells, and has reduced tumor growth in vivo in several preclinical tumor models. Bortezomib has been also shown to cause a delay in tumor growth in in vivo tumor models, including multiple myeloma. Data from in vitro, ex-vivo, and animal models suggest that bortezomib increases osteoblast differentiation and activity, and inhibits osteoclast function. These effects have been observed in bortezomib-treated patients with multiple myeloma affected by an advanced osteolytic disease.
Pharmacokinetics: Bioavailability and Pharmacokinetics: Following the first-dose administration of bortezomib 1 mg/m² and 1.3 mg/m² via intravenous bolus to patients with multiple myeloma and creatinine clearance (CrCl) values >50 mL/min, the mean maximum plasma concentrations of bortezomib (C_max) were 57 and 112 ng/mL, respectively. In subsequent doses, the C_max of bortezomib doses of 1 mg/m² and 1.3 mg/m² ranged from 67 to 106 ng/mL and 89 to 120 ng/mL, respectively.
In patients with multiple myeloma, the total systemic exposure of bortezomib 1.3 mg/m² dose, as measured by the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC_last), was comparable for subcutaneous injection and intravenous bolus administration. The C_max of bortezomib was lower for subcutaneous injection (20.4 ng/mL) compared to intravenous administration (223 ng/mL).
The area under the plasma concentration-time curve (AUC) following subcutaneous injection (92.1 to 195 ng/hr/mL) of bortezomib was equivalent to that of the intravenous injection. An increase in the AUC was observed after multiple-dose intravenous administration at day 11, indicating an increased systemic exposure to bortezomib. The AUC values following intravenous injection of bortezomib ranged from 104 ng/hr/mL at day 1 to 241 ng/hr/mL at day 11. The same trend was also observed following subcutaneous administration of bortezomib.
Bortezomib pharmacokinetics is described by a two-compartment model. Following single- or repeated-dose intravenous administration of 1 mg/m² or 1.3 mg/m² to patients with multiple myeloma, the mean distribution volume (Vd) of bortezomib ranged from 1,659 L to 3,294 L. The mean pseudo-steady state Vd of subcutaneously administered bortezomib was relatively high (1,330 L). Both Vd values indicate that bortezomib is widely distributed to peripheral tissues. In human plasma, the average in-vitro protein of bortezomib in concentration range of 10 to 1,000 ng/mL was 82.9%. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes demonstrated that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. The two deboronated metabolites formed during deboronation (the major metabolic pathway) subsequently undergo hydroxylation to several metabolites. Deboronated metabolites of bortezomib are inactive as 26S proteasome inhibitors.
The mean half-life (t_½) values of bortezomib were 98.1 and 65.7 hours for the intravenous and subcutaneous administration, respectively, with a high degree of intersubject variability. Upon multiple dosing, the mean elimination t_½ of bortezomib ranged from 40 to 193 hours.
Bortezomib is eliminated more rapidly after the first dose compared to succeeding doses. The mean total body clearances following the initial administration of 1 mg/m² and 1.3 mg/m² (102 L/hr and 112 L/hr, respectively) were higher than those observed in subsequent doses (15 to 32 L/h and 18 to 32 L/h, respectively).
Special Populations: Hepatic Impairment: Mild hepatic impairment did not affect the AUC of bortezomib. However, the mean AUC values were increased by approximately 60% in patients with moderate to severe hepatic impairment compared to patients with normal liver function. A lower starting dose is recommended in patients with moderate to severe hepatic impairment (see Dosage & Administration).
Renal Impairment: The pharmacokinetics of bortezomib is not affected by mild to moderate renal impairment (CrCl >20 mL/min/1.73 m²). Exposure of bortezomib from intravenous doses of 0.7 to 1.3 mg/m² (as measured by dose-normalized AUC and C_max) was comparable in patients with mild, moderate, and severe renal impairment. Dialysis may reduce bortezomib concentrations.