Pharmacology: Pharmacodynamics: Bortezomib, an antineoplastic agent, is a reversible inhibitor of 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 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 the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Pharmacokinetics: Absorption/Distribution: Following IV administration of 1 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n = 12 per each dose level), the mean maximum plasma concentrations (Cmax) of bortezomib after the first dose (day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the observed Cmax ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.
The mean distribution volume of bortezomib ranged from approximately 498 to 1,884 L/m2 following single- or repeat-dose administration of 1 or 1.3 mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1,000 ng/mL.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 (CYP-450) isozymes indicate that bortezomib is primarily oxidatively metabolized via CYP-450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP2D6 and CYP2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 and 30 minutes after dosing indicate that the plasma levels of metabolites are low compared with the parent drug.
Excretion: The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.