ARRY 438162

441.2268064

441.23

181R97MR71

DTXSID70209422

C84865

L01EE03|L - Antineoplastic and immunomodulating agents

88.4

3.1

1.67

1.652

P201, P202, P260, P261, P263, P264, P270, P272, P280, P281, P302+P352, P308+P313, P314, P321, P333+P313, P363, P405, P501

H317

Not Classified

The most common (≥25%) adverse reactions in patients receiving the combination of this drug with [Encorafenib] were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. Discontinuation of therapy due to adverse reactions occurred in 5% of patients receiving the combination; the most common reasons were hemorrhage and headache. Due to the variety of adverse events associated with this drug, adverse events are categorized by system: **Systemic events**: Fatigue (31%) **Musculoskeletal system**: Rhabdomyolysis **Ophthalmic events**: Retinal hemorrhage, retinal detachment (6%), macular edema, serous retinopathy (20%) **Circulatory system**: Hypertension, thromboembolic events such as DVT, resulting in pulmonary embolism (5.6%), peripheral edema or periorbital edema (43.5%), hemorrhage (11.2%) **Pulmonary events**: Pneumonitis (1.9%), Pulmonary embolism **Cardiovascular system**: QT interval prolongation (3.3%), Left ventricular dysfunction (7%) **Gastrointestinal system**: Hepatotoxicity, diarrhea, nausea, vomiting, stomatitis, dry mouth **Dermatologic events**: Acneiform dermatitis Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman.

In large clinical trials of the combination of encorafenib and binimetinib, abnormalities in routine liver tests were common and serum ALT elevations occurred in 26% of patients. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 6% and led to dose modification or discontinuation in 3.6% of patients. However, the aminotransferase abnormalities were generally transient and asymptomatic and there were no reports of clinically apparent liver injury with jaundice reported from the prelicensure studies. Since its approval and more widespread use, there have been no published instances of clinically apparent hepatotoxicity attributed to this combination therapy, but the total experience with its use has been limited.

Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72

On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib in combination patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.|Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.|Treatment of colorectal carcinoma|Treatment of melanoma|Drug: Binimetinib

Encorafenib is a selective inhibitor of BRAF kinase that is used in combination with binimetinib, an inhibitor of MEK, in the therapy of metastatic and advanced malignant melanoma. Encorafenib-binimetinib combination therapy is commonly associated with transient elevations in serum aminotransferase levels during therapy, but has yet to be linked to instances of clinically apparent acute liver injury.

Antineoplastic Agents

Binimetinib is a MEK inhibitor. MEK is an enzyme that regulates the biosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. MEK inhibitors interfere with these biosynthetic processes. It is a chemotherapeutic agent that has anti-tumor activity,.

Following oral administration in a pharmacokinetic study, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours. The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure.|Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine.|The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%)|20.2 L/h (24%)

The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.

The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%).

Binimetinib, noncompetitive with ATP, binds to and inhibits the activity of MEK1/2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors. This process can result in the inhibition of growth factor-mediated cell signaling. This may lead to the inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor. MEK1/2 are themselves threonine and tyrosine kinases that possess a dual specificity. They subsequently contribute critically to the activation of the RAS/RAF/MEK/ERK pathway and are typically upregulated in a number of different tumor cell types.

binimetinib

Human drugs -> Mektovi -> 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