12 CLINICAL PHARMACOLOGY
12.1 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.
Following twice weekly administration of 1 mg/m2 and 1.3 mg/m2 bortezomib doses, the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed five minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 mg/m2 and 1.3 mg/m2 doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 dose regimens, respectively.
Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses, the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 ng/mL and 112 ng/mL, respectively. When administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 ng/mL to 106 ng/mL for the 1 mg/m2 dose and 89 ng/mL to 120 ng/mL for the 1.3 mg/m2 dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The AUClast geometric mean ratio (90% confidence interval) was 0.99 (0.80 to 1.23). The Cmax after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL) with repeat dose administration.
The mean distribution volume of bortezomib ranged from approximately 498 L/m2 to 1884 L/m2 following single- or repeat dose administration of 1 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 ng/mL to 1000 ng/mL.
The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 hours to 193 hours after the 1 mg/m2 dose and 76 hours to 108 hours after the 1.3 mg/m2 dose. The mean total body clearance were 102 L/h and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 L/h to 32 L/h following subsequent doses for doses of 1 mg/m2 and 1.3 mg/m2, respectively.
Bortezomib is primarily oxidatively metabolized to several inactive metabolites in vitro via cytochrome P450 (CYP) enzymes 3A4, CYP2C19, and CYP1A2, and to a lesser extent by CYP2D6 and CYP2C9.
No clinically significant differences in the pharmacokinetics of bortezomib were observed based on age, sex, or renal impairment (including patients administered bortezomib after dialysis). The effect of race on bortezomib pharmacokinetics is unknown.
Patients with Hepatic Impairment
Following administration of bortezomib doses ranging from 0.5 to 1.3 mg/m2, mild (total bilirubin ≤1× ULN and AST > ULN, or total bilirubin >1 to 1.5× ULN and any AST) hepatic impairment did not alter dose-normalized bortezomib AUC when compared to patients with normal hepatic function. Dose-normalized mean bortezomib AUC increased by approximately 60% in patients with moderate (total bilirubin >1.5 to 3× ULN and any AST) or severe (total bilirubin >3× ULN and any AST) hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment.
Drug Interaction Studies
No clinically significant differences in bortezomib pharmacokinetics were observed when coadministered with dexamethasone (weak CYP3A4 inducer), omeprazole (strong CYP2C19 inhibitor), or melphalan in combination with prednisone.
Strong CYP3A4 Inhibitor
Coadministration with ketoconazole (strong CYP3A4 inhibitor) increased bortezomib exposure by 35%.