Drug information of Binimetinib

Mechanism of effect

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. binimetinib target kinases in the RAS/RAF/MEK/ERK pathway.

Pharmacodynamic

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.

Pharmacokinetics

Peak plasma time: 1.6 hr

Effect of food

• Administration of a single 45-mg dose with a high-fat, high-calorie meal (consisting of ~150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure

Protein bound: 97%

Vd: 92 L

Metabolism: 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

Half-life: 3.5 hr

Clearance: 20.2 L/hr

Excretion: Feces 62% (32% unchanged); urine 31% (6.5% unchanged)

Drug indications

Melanoma - Metastatic

Dosage

Adult

Melanoma

Indicated in combination with encorafenib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test

45 mg PO BID in combination with encorafenib until disease progression or unacceptable toxicity

Pediatric

Safety and efficacy not established

                              

Side effects

Diarrhea , retinopathy , nausea , abdominal pain , vomiting , vertigo , Hypertension , Peripheral edema , fever , Creatinine increased , hemorrhage , tiredness , Leukopenia , Rash , Hypersensitivity to this drug , Panniculitis

Interactions

Thalidomide , Deferasirox , Lomitapide , Mipomersen , teriflunomide , Panobinostat , Omacetaxine , inotersen , Ibrutinib , Drotrecogin alfa , Ramucirumab , pexidartinib , Cabozantinib , Regorafenib , Ponatinib , Tipranavir , Tositumomab , Ibritumomab tiuxetan , Acalabrutinib , tedizolid , Gefitinib , Dasatinib , Remdesivir , Fidaxomicin

Alerts

venous thromboembolism (VTE) can occur

interstitial lung disease (ILD), including pneumonitis can occur; assess new or progressive unexplained pulmonary symptoms or findings for possible ILD

Hepatotoxicity can occur when binimetinib concomitantly used with encorafenib; monitor liver laboratory tests before initiating, monthly during treatment, and as clinically indicated

Rhabdomyolysis can occur when binimetinib is administered in combination with encorafenib; monitor CPK and creatinine levels prior to initiating treatment, periodically during treatment, and as clinically indicated; withhold, reduce dose, or permanently discontinue based on severity of adverse reaction

Hemorrhage can occur when encorafenib is administered in combination with binimetinib; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage, and hematochezia; withhold, reduce dose, or discontinue drug

Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman

Risks associated with combination treatment; refer to the encorafenib prescribing information for additional risk information

Ocular toxicities

·         Serous retinopathy

• Assess for visual symptoms at each visit
• Perform an ophthalmologic examination at regular intervals for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings

·         Retinal vein occlusion

• Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur
• Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hr

·         Uveitis

• Uveitis (eg, iritis and iridocyclitis) reported in patients treated with binimetinib in combination with encorafenib
• Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings

Cardiomyopathy

• Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, reported in patients treated with binimetinib in combination with encorafenib
• Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2-3 months during treatment
• Safety of binimetinib in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN)
• Closely monitor patients with cardiovascular risk factors

Points of recommendation

• Tell all of your health care providers that you take binimetinib. This includes your doctors, nurses, pharmacists, and dentists.
• High blood pressure has happened with binimetinib. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Blood clots have happened with binimetinib. Tell your doctor if you have ever had a blood clot. Talk with your doctor.
• Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
• Very bad eye problems have happened with binimetinib. Sometimes, this has led to loss of eyesight. Call your doctor right away if you have blurred eyesight, loss of eyesight, or other changes in eyesight. Call your doctor right away if you see color dots or halos or if bright lights bother you.
• Have an eye exam as you have been told by your doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting binimetinib. Talk with your doctor.
• Use birth control that you can trust to prevent pregnancy while taking binimetinib and for at least 1 month after stopping binimetinib.
• If you get pregnant while taking binimetinib or within 1 month after your last dose, call your doctor right away.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking binimetinib as you have been told by your doctor or other health care provider, even if you feel well.
• If you throw up after taking a dose, do not repeat the dose. Take your next dose at your normal time.

• Take a missed dose as soon as you think about it.
• If it is less than 6 hours until the next dose, skip the missed dose and go back to the normal time.
• Do not take 2 doses at the same time or extra doses.

Related drugs

vandetanib , Nintedanib , Sunitinib , Sorafenib , Axitinib , Afatinib , alectinib , brigatinib , Ruxolitinib , vemurafenib , Entrectinib , Cabozantinib , Cobimetinib , Larotrectinib , gilteritinib , Ceritinib , trametinib , encorafenib , midostaurin , pexidartinib , Fedratinib , Crizotinib , Regorafenib , Ponatinib , Dabrafenib , Acalabrutinib , Erdafitinib , Ibrutinib