Cabozantinib

Absorption

After oral administration, peak plasma concentration was achieved in 2-5 hours.

Toxicity

Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage.

Description

Cabozantinib was approved inNovember 2012 for the treatment of patients with progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Cabozantinib was granted orphan drug status by the FDA to facilitate development of newtreatment options for patients with MTC. It is a member of a class of tyrosine kinase inhibitors (TKIs) with nanomolar pan-inhibitory activity against VEGFR2, MET, and RET among others. Inhibition of the VEGF pathway has been shown preclinically to initially slow tumor growth, but rapid revascularization is followed by aggressive tumor growth. The MET pathway has been implicated in the development of VEGF resistance, so dual VEGF/MET activity is viewed as desirable. In addition, mutations in RET play a particular role in MTC, with 25% of the tumors inheriting a germlinemutation in the proto-oncogene, so multiple tyrosine kinase inhibition may be viewed as particularly beneficial for the treatment of MTC.

Originator

Exelixis (United States)

The Uses of Cabozantinib

Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively

The Uses of Cabozantinib

XL184 can be used in biological study. Computational network biological approach based on pathway cross-talk inhibition identified new synergistic drug combinations using raloxifene and cabozantinib for treatment of human breast cancer in xenograft mouse model. Potent c-MET inhibitor.

What are the applications of Application

XL-184 free base is a potent VEGFR2 and Met inhibitor

Background

Cabozantinib was first approved in 2012 and is a non-specific tyrosine kinase inhibitor. It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer. In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in 2019 for the treatment of hepatocellular carcinoma in previously treated patients.

Indications

Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib.

Definition

ChEBI: A dicarboxylic acid diamide that is N-phenyl-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in which the hydrogen at position 4 on the phenyl ring is substituted by a (6,7-dimethoxyquinolin-4-yl)oxy group. A multi-t rosine kinase inhibitor, used (as its malate salt) for the treatment of progressive, metastatic, medullary thyroid cancer.

brand name

Cometriq

General Description

Class:receptor tyrosine kinase; Treatment: MTC; RCC; HCC; Other name: XL-184, BMS-907351; Elimination half-life = 110 h; Protein binding > 99.7%

Pharmacokinetics

Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.

Clinical Use

Cabozantinib (PF-06463922; brand name Cabometyx; Exelixis, Alameda, CA) is an oral multikinase inhibitor with CNS penetration. It is FDA approved for use in medullary thyroid cancer and as a second-line agent in advanced renal cell carcinoma. In vitro studies found it to exhibit excellent activity against both the wild-type ROS1 fusion and the G2032R and G2026M mutations at concentrations less than 30?nmol/L—a dose much lower than what is clinically achievable [71, 91]. It has been found to inhibit CD74-ROS1-transformed Ba/F3 cells with more potency than entrectinib, brigatinib, lorlatinib [92], or foretinib [71].

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by clarithromycin and erythromycin; concentration reduced by rifampicin - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone - avoid.
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

Metabolism

Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite.

Metabolism

Cabozantinib is metabolised mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzymes produce an N-oxide metabolite. Cabozantinib is eliminated mainly by the faeces (54%) and also by the urine (27%).

storage

Store at +4°C

References

1) Yakes?et al.?(2011),?Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth; Mol. Cancer Ther.,?10?2298 2) You?et al.?(2011),?VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer; Cancer Res.,?71?4758 3) Kurzrock?et al.?(2011),?Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor in patients with medullary thyroid cancer; J. Clin. Oncol.,?29?2660