Source of information: Drugbank (External Link). Last updated on: 3rd July 18
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Active Ingredient / Synonyms
Carfilzomib | Carfilzomib |
Carfilzomib is an injectable antineoplastic agent (IV only). Chemically, it is a modified tetrapeptidyl epoxide and an analog of epoxomicin. It is also a selective proteasome inhibitor. FDA approved on July 20, 2012.
Carfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate.
Mechanism of Action
Carfilzomib is made up of four modified peptides and acts as a proteasome inhibitor. Carfilzomib irreversibly and selectively binds to N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This 20S core has 3 catalytic active sites: the chymotrypsin, trypsin, and caspase-like sites. Inhibition of the chymotrypsin-like site by carfilzomib (β5 and β5i subunits) is the most effective target in decreasing cellular proliferation, ultimately resulting in cell cycle arrest and apoptosis of cancerous cells. At higher doses, carfilzomib will inhibit the trypsin-and capase-like sites.
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor. Furthermore, studies suggest that carfilzomib is more potent than bortezomib.
Cmax, single IV dose of 27 mg/m^2 = 4232 ng/mL; AUC, single IV dose of 27 mg/m^2 = 379 ng•hr/mL; Carfilzomib does not accumulation in the systemic. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure.
Vd, steady state, 20 mg/m^2 = 28 L
Carfilzomib was rapidly and extensively metabolized by the liver. The predominant metabolites were the peptide fragments and the diol of carfilzomib which suggests that the main metabolic pathways are peptidase cleavage and epoxide hydrolysis. The cytochrome P450 enzyme system is minimally involved in the metabolism of carfilzomib. All metabolites are inactive.
Following intravenous administration of doses ≥ 15 mg/m^2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1.
Systemic clearance = 151 - 263 L/hour. As this value exceeds hepatic blood flow, it suggests that carfilozmib is cleared extrahepatically.
Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. The two dose limiting toxicities are thrombocytopenia and febrile neutropenia. Maximum tolerate dose = 15 mg/m^2
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