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The SARfaris: GPCR, Kinase, ADME

Sunday, 6 January 2013

New Drug Approvals 2012 - Pt. XXVI - cabozantinib (COMETRIQTM)

ATC code: not yet assigned
Wikipedia: Cabozantinib

On November 29th, the FDA approved  CometriqTM(cabozantinib, research code XL-184) for the treatment of patients with progressive, metastatic, medullary thyroid cancer (MTC). MTC is a rare type of thyroid cancer accounting for 5-10% of all diagnosed thyroid cancers (CRUK). A quarter of MTC cases are familial and are caused by a mutation in the RET gene. Clinical studies showed that cabozantinib increases progression-free survival time to 11.2 months in comparison with 4 months for placebo.

Cabozantinib (research codes: XL-184, BMS-907351; IUPAC: Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, Standard InChI: ONIQOQHATWINJY-UHFFFAOYSA-N) is dosed as the (S)-malate salt. The parent molecule, cabozantinib, has a molecular weight of 501.5 and a ACD/LogP of 3.08. The effective half-life is ~55 hours, the oral volume of distribution (V/F) is ~349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.

Cabozantinib has been given a boxed warning due to sever, sometimes fatal haemorrhaging in 3% of patients and gastrointestinal perforations in 3% and fistula formation in 1% of treated patients.

Cabozantinib is a multi-kinase inhibitor, and inhibits the following tyrosine kinases in vitro: RET (P07949), MET (P08581), FLT1 (aka VEGFR1, P17948), KDR (aka VEGFR2, P35968), FLT4 (aka VEGFR3, P35916), KIT (P10721), NTRK2 (TRKB Q16620), FLT3 (P36888), AXL (P30530), and TEK (aka TIE2, Q02763).

Prescribing information can be found here.

The license holder for CometriqTM is Exelexis Inc and the product website can be found here

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