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Proteoz Actions |
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Proteoz 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 active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Proteoz is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, Proteoz appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).
Before receiving Proteoz, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.
You will receive Proteoz while you are in a hospital or cancer treatment center. A nurse or other trained health professional will give you Proteoz. Proteoz is given through a needle placed in one of your veins or as a shot under your skin (usually in the abdomen or thighs).
You may also receive medicines to help prevent nausea, vomiting, or diarrhea. Ask your doctor or other health caregiver if you should drink extra water while you are using Proteoz. This could help you avoid feeling dizzy or lightheaded.
If you are using Proteoz for multiple myeloma, it is important to tell your doctor if you have received Proteoz in the past.
Note: The reconstituted concentrations for IV and SubQ administration are different; use caution when calculating the volume for each route and dose. Consider SubQ administration in patients with preexisting or at high risk for peripheral neuropathy.
IV: Administer via rapid IV push (3 to 5 seconds). When administering in combination with rituximab for first-line therapy of mantle cell lymphoma, administer Proteoz prior to rituximab.
SubQ (Velcade only): Subcutaneous administration of Proteoz 1.3 mg/m days 1, 4, 8, and 11 of a 21-day treatment cycle has been studied in a limited number of patients with relapsed multiple myeloma; doses were administered subcutaneously (concentration of 2.5 mg/mL) into the thigh or abdomen, rotating the injection site with each dose; injections at the same site within a single cycle were avoided (Moreau 2010; Moreau 2011). Response rates were similar to IV administration; decreased incidence of grade 3 or higher adverse events were observed with SubQ administration. Administer at least 1 inch from an old site and never administer to tender, bruised, erythematous, or indurated sites. If injection site reaction occurs, the more dilute 1 mg/mL concentration may be used SubQ (or IV administration of 1 mg/mL concentration may be considered).
For SubQ (Velcade) or IV administration only; fatalities have been reported with inadvertent intrathecal administration. Proteoz should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration.
Note: The generic product (Fresenius Kabi) is NOT approved for subcutaneous administration.
Proteoz 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 Proteoz is cytotoxic to a variety of cancer cell types in vitro. Proteoz 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 Proteoz doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed 5 minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 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 Proteoz (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/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.
Distribution:
The mean distribution volume of Proteoz ranged from approximately 498 to 1884 L/m2 following single- or multiple-dose administration of 1 mg/m2 or 1.3 mg/m2.
The binding of Proteoz to human plasma proteins averaged 83% over the concentration range of 100 to 1,000 ng/mL.
Elimination:
The mean elimination half-life of Proteoz after 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 clearances was 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 and 1.3 mg/m2, respectively.
Metabolism: The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated Proteoz 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.
In vitro studies indicate that Proteoz is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2.
Excretion: The pathways of elimination of Proteoz have not been characterized in humans.
Specific Populations:
Age: Analyses of data after the first dose of Cycle 1 (Day 1) in patients who had received intravenous doses of 1 mg/m2 and 1.3 mg/m2 showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients less than 65 years of age had about 25% lower mean dose-normalized AUC and Cmax than those greater than or equal to 65 years of age.
Sex: Sex has no clinically important effect on Proteoz exposure.
Hepatic Impairment: Mild hepatic impairment had no clinically important effect on dose-normalized AUC or Cmax. The dose-normalized mean AUC was increased by approximately 60% in patients with moderate hepatic impairment (defined as total bilirubin greater than 1.5 to 3 times the upper limit of normal and any AST) or severe hepatic impairment (defined as total bilirubin greater than 3 times the upper limit of normal and any AST).
Renal Impairment: Dose-normalized AUC and Cmax was comparable for patients with creatinine clearance (CLcr) from 59 mL/min/1.73 m2 to less than 20 mL/min/1.73 m2 compared to patients with CLcr greater than or equal to 60 mL/min/1.73 m2.
Drug Interaction Studies
Effect of Other Drugs on Proteoz: The coadministration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of Proteoz.
The coadministration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of Proteoz by 35%.
The coadministration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of Proteoz by at least 45%. Decreases greater than 45% may occur, as the drug interaction trial was not designed to evaluate the maximum effect of rifampin on Proteoz exposure.
Effect of Proteoz on Other Drugs: Proteoz inhibits CYP2C19 activity in vitro and the coadministration of Proteoz for injection with sensitive or narrow therapeutic CYP2C19 substrates may increase their exposure. Proteoz did not inhibit CYP1A2, 2C9, 2D6, or 3A4 in vitro.
Proteoz did not induce the CYP3A4 or 1A2 activity in vitro.
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Information checked by Dr. Sachin Kumar, MD Pharmacology
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