Velcade 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 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: Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to eleven patients with multiple myeloma, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively. 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 mean elimination half-life 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 following subsequent doses for doses of 1.0 mg/m² and 1.3 mg/m², respectively.
In the PK/PD substudy in Phase 3 trial, following an IV bolus or subcutaneous (SC) injection of a 1.3 mg/m² dose to multiple myeloma patients (n = 14 for IV, n = 17 for SC), the total systemic exposure after repeat dose administration (AUC_last) was equivalent for SC and IV administration. The C_max after SC administration (20.4 ng/mL) was lower than IV (223 ng/mL). The AUC_last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 122.80%.
Distribution: The mean distribution volume of bortezomib ranged from 1659 liters to 3294 liters single- or repeat dose IV 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. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 - 1000 ng/mL.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. 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. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
Special Populations: Age, Gender, and Race: The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m² doses to 104 pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m², volume of distribution at steady-state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. 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.
The effects of gender, and race on the pharmacokinetics of bortezomib have not been evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of IV bortezomib was assessed in 60 cancer patients 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 (see Table 7).
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees 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, n = 12), Mild (CrCL = 40 - 59 mL/min/1.73 m², n = 10), Moderate (CrCL = 20 - 39 mL/min/1.73 m², n = 9), and Severe (CrCL < 20 mL/min/1.73 m², n = 3). A group of dialysis patients who were dosed after dialysis was also included in the study (n = 8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and C_max) was comparable among all the groups (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m² (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m². VELCADE could have a potential effect on either male or female fertility.