Bortezomib

Bortezomib (velcade); (1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2 -[pyrazinylcarbonyl)amino] propyl]butyl]boronic acid binds to the 20S core of the 26S proteasome and reversibly inhibits its chymotrypsin-like activity. Inhibition of the proteasome disrupts multiple signaling cascades within the cell, often leading to cell death. The most important consequences of proteasome inhibition are believed to result from downregulation of NF-kB, a key transcription factor that promotes cell survival. In a similar manner, bortezomib disrupts ubiquitin-proteasome regulation of p21, p27, and p53, which are key regulatory proteins in the cell cycle and initiators of apoptosis. The antineoplastic activity of bortezomib in tumors is likely due to a greater dependence on cell proliferating pathways in cancer relative to normal tissues.

After intravenous administration of 1—1.3 mg/m2 of bortezomib in patients without renal or hepatic impairment, there is a rapid distribution phase (<10 minutes), followed by a longer elimination phase of 5—15 hours. Plasma protein binding averaged 83%. The mean terminal elimination in preclinical studies was 5.4 hours, with an average clearance of 66 L/h. Peak pharmacodynamic activity (proteasome inhibition) occurred at 1 hour with a mean of 61% inhibition and a t122 of ~24 hours. Inhibition of the 20S subunit was 10—30% at 96 hours. Proteasome inhibition is highly concentration dependent.

Bortezomib is primarily metabolized to an inactive metabolite by hepatic CYPs. Deborona-tion accounts for >90% of total metabolism, with CYP3A4 being more active than CYP2D6. Ongoing studies in patients with hepatic or renal impairment should define pathways of elimination that will help guide dose reduction in such patients. Bortezomib is a poor inhibitor of hepatic CYPs.

Bortezomib is available for intravenous injection only. Each vial contains 3.5 mg of borte-zomib as a sterile lyophilized powder and 35 mg of mannitol. Prior to use, the contents of each vial are reconstituted with 3.5 mL of normal (0.9%) saline. The reconstituted product should be clear and colorless and should be administered to patients within 8 hours. The recommended starting dose of bortezomib is 1.3 mg/m2 given as an intravenous bolus, and this should be given on days 1, 4, 8, and 11 of every 21-day cycle (10-day rest period per cycle). At least 72 hours should elapse between doses. For severe nonhematologic and hematologic toxicities, the drug should be held until resolution and subsequent doses should be reduced by 25%. In clinical trials, some patients have received 2 mg/m2 without severe toxicity.

Bortezomib is FDA-approved for patients with MM who have received 2 prior therapies and are progressing on their current therapy. The drug is being studied in combination with other drugs in MM as well as other hematologic neoplasms and solid tumors. Escalating doses of bortezomib have resulted in dose-limiting GI, hematopoietic, lymphatic, and renal toxicities. At the standard dose and schedule, serious toxicities encountered in >5% of patients included thrombocytopenia, fatigue, peripheral neuropathy, neutropenia, anemia, nausea and vomiting, diarrhea, limb pain, dehydration, and weakness. Peripheral neuropathy was encountered more frequently in patients with a prior history of neuropathy or preexisting numbness, pain, or burning, where dose reductions of bortezomib are recommended. Usually, the neuropathy improves or resolves completely after several months off treatment. Hypotension associated with the injection of bortezomib has been rarely encountered, and caution should be taken with patients who are volume-depleted, have a history of syncope, or who are on antihypertensive medications.

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