Bortecade Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S 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 cell. This disruption of normal homeostatic mechanism can lead to cell death.
Pharmacokinetics: Hepatic Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with hepatic impairment (see Precautions).
Renal Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with renal impairment. Clinical studies included patients with creatinine clearance values ranging from 13.8 to 220 mL/min (see Precautions).
Pediatric: There are no pharmacokinetic data in pediatric patients.
Drug Interactions: No formal drug interaction studies have been conducted with bortezomib.
Bortezomib is a substrate of cytochrome P450 3A4, 2C19, and 1A2 (see Precautions). Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of >30 μM (>11.5 μg/mL). Bortezomib may inhibit 2C19 activity (ICSD=18 μM, 6.9 μg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes. Patients who are concomitantly receiving Bortecade and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.