Bortezomib (Page 5 of 8)

8.6 Renal Impairment

No starting dosage adjustment of Bortezomib Injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib Injection should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No starting dosage adjustment of Bortezomib Injection is recommended for patients with mild hepatic impairment (total bilirubin ≤1× ULN and AST > ULN, or total bilirubin >1 to 1.5× ULN and any AST). The exposure of bortezomib is increased in patients with moderate (total bilirubin ≥1.5 to 3× ULN and any AST) and severe (total bilirubin >3× ULN and any AST) hepatic impairment. Reduce the starting dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

8.8 Patients with Diabetes

During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib Injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.

10 OVERDOSAGE

There is no known specific antidote for Bortezomib Injection overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given.

Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m ² basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m ² and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour postadministration, with progression to death in 12 to 14 hours following drug administration.

11 DESCRIPTION

Bortezomib Injection contains bortezomib which is a proteasome inhibitor. Bortezomib is a modified dipeptidyl boronic acid. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid.

Bortezomib has the following chemical structure:

The molecular weight is 384.24. The molecular formula is C ₁₉ H ₂₅ BN ₄ O ₄ . The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.

Bortezomib Injection is available as a ready-to-use sterile solution for intravenous injection:

• Each mL of the 3.5 mg/3.5 mL (1 mg/mL) strength contains 1 mg of bortezomib, 10 mg mannitol, 0.82 mg sodium acetate, 20 mg dimethyl sulfoxide, in water for injection in a 5 mL single-dose vial. The pH may have been adjusted with hydrochloric acid or sodium hydroxide.
• Each mL of the 3.5 mg/1.4 mg/mL (2.5 mg/mL) strength contains 2.5 mg of bortezomib, 25 mg mannitol, 0.82 mg sodium acetate, 22 mg dimethyl sulfoxide, in water for injection in a 2 mL single-dose vial. The pH may have been adjusted with hydrochloric acid or sodium hydroxide.

bortezomib-structure

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.

12.2 Pharmacodynamics

Following twice weekly administration of 1 mg/m ² and 1.3 mg/m ² 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 and 1.3 mg/m ² doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m ² and 1.3 mg/m ² dose regimens, respectively.

12.3 Pharmacokinetics

Following intravenous administration of 1 mg/m ² and 1.3 mg/m ² doses, the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. When administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m ² dose and 89 to 120 ng/mL for the 1.3 mg/m ² dose.

Distribution

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m ² following single- or repeat-dose administration of 1 mg/m ² or 1.3 mg/m ² to patients with multiple myeloma. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.

Elimination

The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m ² dose and 76 to 108 hours after the 1.3 mg/m ² dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 mg/m ² and 1.3 mg/m ² , respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m ² , respectively.

Metabolism

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.

Excretion

The pathways of elimination of bortezomib have not been characterized in humans.

Specific Populations

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/m ² , 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

Clinical 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%.

Strong CYP3A4 inducer

Coadministration with rifampin (strong CYP3A4 inducer) decreased bortezomib exposure by approximately 45%.

In Vitro Studies

Bortezomib may inhibit CYP2C19 activity and increase exposure to drugs that are substrates for this enzyme.