Retrox Mechanism of Action



Idaman Pharma


Pharmaniaga Logistics
Full Prescribing Info
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents. ATC Code: L01XG01.
Pharmacology: Pharmacodynamics: Mechanism of action: Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.
Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t½ of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible.
Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.
Bortezomib increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.
Pharmacokinetics: Absorption: The mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to patients with multiple myeloma. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.
The total systemic exposure after repeat dose administration dose of 1.3 mg/m2 was equivalent for SC and IV administration. The Cmax after SC administration was lower than IV.
Distribution: The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l following single- or repeated-dose intravenous administration of 1.0 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
Biotransformation: Bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Elimination: The mean elimination half-life (t½) of bortezomib upon multiple dosing ranged from 40-193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively.
Special populations: Hepatic impairment: The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in patients primarily with solid tumors and varying degrees of hepatic impairment at bortezomib doses ranging from 0.5 to 1.3 mg/m2.
When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalised bortezomib AUC. However, the dose normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely.
Renal impairment: Exposure of bortezomib (dose-normalized AUC and Cmax) was comparable among all the groups of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥60 mL/min/1.73 m2), Mild (CrCL=40-59 mL/min/1.73 m2), Moderate (CrCL=20-39 mL/min/1.73 m2), and Severe (CrCL <20 mL/min/1.73 m2). A group of dialysis patients who were dosed after dialysis was also included. Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly.
Age: The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m2 doses to pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Clearance of bortezomib increased with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
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