Carfilzomib, a proteasome inhibitor, is indicated for the treatment of patients with multiple myeloma.
Multiple myeloma (multiple myeloma, MM) is a malignant tumor originating from the B cell lineage, characterized by the clonal proliferation of malignant plasma cells in the bone marrow microenvironment, causing fractures and bone marrow failure, and is the second most common blood system disease in the world Tumors cannot be cured by traditional chemotherapy regimens.
Bortezomib is the first proteasome inhibitor and the first-line drug for multiple myeloma, which has made a breakthrough in the treatment of multiple myeloma. Due to its strong drug resistance and people's resistance to it Continuous research on drug mechanism, carfilzomib was approved by the FDA as the second proteasome inhibitor after bortezomib, and received at least 2 drugs before treatment (including bortezomib and immunomodulators) ) patients with multiple myeloma. Carfilzomib is a specific, irreversible targeted inhibitor originally developed by Proteolix, produced by Onyx Pharmaceuticals, and approved by the FDA on July 20, 2012.
(1) Mechanism of action of carfilzomib
Carfilzomib binds irreversibly to the chylase of the 20S proteasome, whereas bortezomil binds reversibly. In addition, carfilzomib also inhibits trypsin and semi-acyl-like aspartase. Irreversible inhibition and selective inhibition confer a potential advantage over bortezomib in both efficacy and tolerability. Carfilzomib’s structure and mechanism of action are different from that of bortezomib, the dipeptide boric acid analogous. Bortezomib reversibly binds to the catalytic β5 subgroup of the proteasome, while the catalytic β5 subgroup and the immune proteasome β5i(LMP7) subgroup of cafezomib irreversibly covalently binds to the proteasome, which have better potency and resistance compared to bortezomib.
(2) Safety and Tolerability
Compared with bortezomib, carfilzomib had less peripheral neuropathy. In RRMM patients, the rate of grade 3 peripheral neuropathy was 1.3%, but no patients had grade 4 events, and only 1% of patients required dose adjustment or Withdrawal. Long-term treatment with carfilzomib did not increase the risk of psychosis.
(3) Drug resistance
About 60% of patients will eventually develop resistance to bortezomib, and the average time for drug resistance to appear is within one year of bortezomib administration. Clinical studies have shown that carfilzomib is safe to replace bortezomib and can effectively treat MM patients who failed bortezomib treatment.
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