Cobimetinib

531.31

531.31

ER29L26N1X

DTXSID60239435

C68923

L01XE38|L - Antineoplastic and immunomodulating agents

44.37000

5.39600

1.706

565.9±50.0 °C(Predicted)

13.13±0.20

The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting.

Elevations in serum aminotransferase and alkaline phosphatase levels are common during vemurafenib therapy and are even more common when it is combined with cobimetinib, abnormal liver tests occurring in 26% to 70% of treated patients and ALT values rising above 5 times the upper limit of the normal range (ULN) in 6% to 12%. Instances of clinically apparent liver injury with jaundice have also been reported during the clinical trials of cobimetinib and vemurafenib therapy, but the clinical features, course and outcomes of these episodes have not been described in detail. At least one instance of hepatocellular injury with jaundice was included in the initial safety review of cobimetinib. The MAPK pathway inhibitors as a class are often associated with transient serum enzyme elevations and more rarely with instances of clinically apparent liver injury, but the clinical features have not been described and the association with cobimetinib not clearly defined. The rate of clinically significant liver injury and hepatic failure associated with protein kinase inhibitors is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden.

95% bound to human plasma protein.

For the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Cobimetinib is used in combination with vemurafenib, a BRAF inhibitor.|FDA Label|Cotellic is indicated for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.|Treatment of all conditions included in the category of malignant neoplasms (except haematopoietic and lymphoid tissue) with Ras, Raf or MEK pathway activation|Drug: Cobimetinib

Cobimetinib is a tyrosine kinase receptor inhibitor that is used in combination with vemurafenib as therapy for selected forms of advanced malignant melanoma. The combination of cobimetinib and vemurafenib is commonly associated with serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.

Antineoplastic Agents

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signalling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors becomes BRAF-inhibitor resistant due to reactivation of MAPK signalling. BRAF-inhibitor resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK.

The bioavailability of cobimetinib is 46%, the AUC and Cmax is unaffected by food.|76% of the dose was recovered in feces with 6.6% as unchanged drug. 17.8% of the dose was recovered in urine with 1.6% as unchanged drug.|806L in cancer patients based on a population PK analysis.|13.9L/h

Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed.

Average half life was 44 hours.

MEK inhibitor Cobimetinib specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway.

(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone

Human drugs -> Cotellic -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients