Carfilzomib (PR-171) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Carfilzomib (PR-171) induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. In clinical trials, carfilzomib (PR-171) has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. At clinically relevant concentrations, carfilzomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Carfilzomib is currently in a phase III confirmatory clinical trial, known as the ASPIRE trial, comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 45 mg/mL|
The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects.
Hurchla MA, et al. Leukemia. 2013 Feb;27(2):430-40. PMID: 22763387.
Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo.
Dasmahapatra G, et al. Mol Cancer Ther. 2011 Sep;10(9):1686-97. PMID: 21750224.
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.
Kuhn DJ, et al. Blood. 2007 Nov 1;110(9):3281-90. PMID: 17591945.
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