Proteasome Inhibitors

April 2, 2007

bortezomib, Velcade, PR-171, PS-341, NPI-0052, Drug inhibits the action of proteasomes, which normally break down proteins that have been ubiquinated or tagged for destruction, such as p53, the "guardian of the genome," and cell cycle proteins.

 

FDA-Approved Drugs: bortezomib (Velcade)

Investigational Drugs: PR-171, PS-341, NPI-0052

Mechanism of Action

Drug inhibits the action of proteasomes, which normally break down proteins that have been ubiquinated or tagged for destruction, such as p53, the "guardian of the genome," and cell cycle proteins. By blocking this proteasome, there is loss of homeostasis in multiple signaling cascades, and this leads to the slowing of malignant cell growth, cell cycle arrest, and promotion of apoptosis, or programmed cell death of malignant cells. Drug inhibits NF-&kgr;B transcriptional activity, so may also have antiangiogenic and antimetastatic properties.

Metabolism

Cytochrome P450 microenzyme system (3A4, 2C19, 1A2); elimination route is unknown but elimination half-life following first dose is 9 to 15 hours. Drug is widely distributed, and > 80% of the drug is protein-bound.

Indications

Bortezomib is US Food and Drug Administration (FDA)-indicated for the treatment of patients who have received at least one prior therapy for (1) multiple myeloma, and (2) mantle cell non-Hodgkin's lymphoma (NHL).

Off Label Uses or Other Uses

Patients with relapsed, refractory NHL.

Patient Education

Teach patient to (1) use effective contraception; (2) avoid breast feeding while receiving the drug; (3) avoid taking any over-the-counter medications without first discussing with nurse or physician, including aspirin and nonsteroidal anti-inflammatory drugs; (4) self-assess and report neuropathy or neuropathic pain; (5) self-assess and report signs and symptoms of bleeding; and (6) report right away, or seek medical attention, for nausea, vomiting, diarrhea that does not respond to intervention, bleeding, dehydration, feeling faint.

Interactions

(1) Hypoglycemic agents: may have increased or decreased effect; monitor patient's blood glucose closely and titrate dose based on result; (2) inhibitors of cytochrome P450 3A4 microenzyme (theoretically can increase serum level of bortezomib): eg, ketoconazole, itraconazole, clarithromycin, diltiazem, grapefruit juice; avoid concomitant administration; monitor closely for toxicity; (3) inducers of cytochrome P450 3A4 microenzyme (theoretically can decrease effect of bortezomib): eg, rifampin, carbamazepine, phenytoin; do not coadminister if possible; (4) dexamethasone: synergy in patients with multiple myeloma.

Special Considerations

(1) Stop drug for grade 3 nonhematologic or grade 4 hematologic toxicity; (2) dose modifications required for thrombocytopenia, peripheral neuropathy, neuropathic pain, other grade 3/4 toxicity requiring drug suspension; (3) closely monitor patients with preexisting peripheral neuropathy for worsening, and pain as drug may need to be interrupted; (4) monitor platelet count closely.

Contraindications/Precautions

(1) Allergy to bortezomib, boron, mannitol; (2) pregnancy (category D); (3) use cautiously in patients with renal or hepatic dysfunction, peripheral neuropathy, hypotension, or history of syncope.

Adverse Reactions by System (vary with drug)

CNS: Dizziness, headache, insomnia, syncope, rare
agitation, confusion, change in mental status

CV: Hypotension, edema, rare congestive heart failure, rare cardiac arrest, rare arrythmia

EENT: Diplopia, blurred vision, decreased hearing, vertigo

GI: Nausea, vomiting, dehydration, diarrhea, constipation, abdominal pain

GU: Renal calculi, bladder spasm, incontinence, urinary retention

Hematologic: Thrombocytopenia, anemia, neutropenia

Metabolic: Hypocalcemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia, hyperuricemia

Musculoskeletal: Arthralgia, myalgia, muscle cramps

Respiratory: Dyspnea, cough

Skin: Rash, herpes zoster

Other: Fever, peripheral neuropathy, paresthesia, dysesthesia