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The SARfaris: GPCR, Kinase, ADME

Sunday, 22 July 2012

New Drug Approvals 2012 - Pt. XV - Carfilzomib (KyorolisTM )

ATC Code: L01XX
Wikipedia: Carfilzomib
On July 20th 2012 the FDA approved Carfilzomib (KyorolisTM) for the treatment of patients with multiple myeloma who have received prior therapies including bortezomib and an immunomodulatory therapy, and who have demonstrated disease progression within 60 days of completion of the previous therapy. Multiple myeloma is a cancer of the Plasma Cells and usually in the bone marrow. Five year survival is about 40% in the UK and and the USA.

Carfilzomib is a chirally defined modified tetrapeptidyl epoxide substrate analogue with a molecular weight of 719.9. The molecular formula is C40H57N5O7. (SMILES= O=C(N[C@H](C(=O)N[C@H](C(=O)N[C@H(C(=O)N[C@H](C(=O)[C@@]1(OC1)C)CC(C)C)Cc2ccccc2)CC(C)C)CCc3ccccc3)CN4CCOCC4)

Cmax and AUC following a single intravenous dose of 27 mg/m2 was 4,232 ng/mL and 379, respectively. The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. Carfilzomib was rapidly and extensively metabolised, via peptidases and epoxide hydrolyses - i.e. non-CYP mediated metabolism. After intravenous administration of ≥ 15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour.

Carfilzomib is a second generation, non-competitive, irreversible proteasome inhibitor. It contains the unusual (for drugs) epoxide group responsible for the irreversible binding to the target. It is differentiated from the first generation proteasome inhibitor bortezomib (boron-based) in this irreversible inhibition mechanism, which is believed to contribute to overcoming bortezomib resistance. Additionally, clinical trials have showed that carfilzomib is associated with fewer incidences of Peripheral Neuropathy (NP) (incidence reported 14% of patients with 1% having Grade 3 NP) in comparison with bortezomib (36% and 24% Grade 3). Epoxides are quite reactive, and can react with many proteins in a biological system.

The molecular target for carfilzomib is the 20S catalytic core of the large multi-protein complex - the proteasome. Specifically, it binds to the N-terminal threonine-containing active site of the endopeptidase proteasome subunit beta type-7 (Uniprot: Q99436).

The amino acid sequence is:

>sp|Q99436|PSB7_HUMAN Proteasome subunit beta type-7 OS=Homo sapiens GN=PSMB7 PE=1 SV=1

Prescribing information had be found here.

The licence holder is Onyx Pharmaceuticals and the product website is

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