Mektovi (binimetinib)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Binimetinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent.
Binimetinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2, is an antineoplastic agent. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Approximately 40-60% of cutaneous melanomas carry a b-Raf serine-threonine kinase (BRAF) mutation.
The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E); a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K). BRAF V600 mutations result in activation of the BRAF pathway that includes MEK 1 and 2. The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).
In vitro studies have demonstrated that binimetinib inhibits phosphorylation of ERK in cell-free assays and MEK-dependent phosphorylation of melanoma cells harboring BRAF mutation. The drug also has demonstrated inhibition of ERK phosphorylation and tumor growth in xenograft models of melanoma harboring BRAF mutation in mice.
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway. Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib). In vitro, use of binimetinib in combination with encorafenib resulted in increased antiproliferative activity compared with either drug alone in BRAF mutation-positive cell lines.
The combination of binimetinib and encorafenib also has demonstrated increased inhibition of tumor growth and delayed emergence of resistance compared with either drug alone in xenograft models of melanoma harboring BRAF V600E mutation in mice.
Following oral administration of binimetinib 45 mg twice daily, at least 50% of the dose is rapidly absorbed with peak plasma concentrations occurring in 1.6 hours. Peak plasma concentrations and systemic exposure of binimetinib and its active metabolite (M3) are proportional to dose following single or repeated administration of the drug over the dosage range of 5-80 mg or 5-60 mg once daily, respectively. Repeated administration of binimetinib 45 mg twice daily resulted in a 1.5-fold binimetinib accumulation ratio.
Administration of a single 45-mg dose of binimetinib with a high-fat, high-calorie meal (approximately 150 calories from protein, 350 calories from carbohydrates, 500 calories from fat) did not affect systemic exposure of the drug in healthy individuals. Binimetinib is highly bound (97%) to plasma proteins. The mean terminal half-life of binimetinib is 3.5 hours.
Binimetinib is metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and, to a lesser extent, by N-dealkylation and amide hydrolysis by cytochrome P-450 (CYP) isoenzymes 1A2 and 2C19 to form its minor active metabolite (M3). Following oral administration of a single radiolabeled dose of binimetinib, 62% of the radioactivity was recovered in feces (32% of the dose as unchanged drug) and 31% was recovered in urine (6.5% of the dose as unchanged drug). Single agent MEK inhibitor treatment is no longer recommended by experts as combination BRAF/MEK inhibition has demonstrated superior outcomes with a similar safety profile.
The pharmacokinetics of binimetinib do not appear to be affected substantially by age (20-94 years), gender, body weight, or UGT1A1 genotype.
USES: This medication is used to treat certain types of cancer (such as lung cancer, melanoma skin cancer). Binimetinib belongs to a class of drugs known as kinase inhibitors. It works by slowing or stopping the growth of cancer cells.
Generic name: binimetinib
Pronunciation: (BIN-i-ME-ti-nib)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Mektovi
Indications
The following indications are listed for Mektovi:
- Malignant Melanoma With Braf V600e Mutation
- Malignant Melanoma With Braf V600k Mutation
- Non-Small Cell Lung Cancer With Braf V600e Mutation
Also known as: Melanoma With Braf V600e Genetic Mutation, Nsclc With Braf V600e Mutation.
Dosing
If adverse reactions occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of binimetinib may be required based on severity of the reaction. If dosage modification of binimetinib for adverse reactions is necessary, a dosage reduction to 30 mg twice daily is initially recommended. If a dosage of 30 mg twice daily is not tolerated, binimetinib should be permanently discontinued.
Binimetinib is administered orally twice daily, with doses given approximately 12 hours apart; the drug can be taken without regard to meals.
If a dose of binimetinib is missed by more than 6 hours, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time. Patients should not take extra tablets of the drug to make up for the missed dose.
If vomiting occurs following administration of binimetinib, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.
Store at 20-25oC (excursions permitted between 15-30oC).
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Drug interactions
Binimetinib is metabolized principally by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and, to a lesser extent, by cytochrome P-450 (CYP) isoenzymes 1A2 and 2C19 to form a minor active metabolite (M3). Binimetinib is a weak inhibitor of UGT1A. The drug does not demonstrate time-dependent inhibition of CYP isoenzymes 1A2, 2C9, 2D6, and 3A, and shows little to no induction of CYP2C9.
In vitro studies indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); the drug is not a substrate of organic cation transporter (OCT) 1 or organic anion transport protein (OATP) 1B1, OATP1B3, and OATP2B1. In vitro, binimetinib is a weak inhibitor of OCT2, but does not inhibit OCT1.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*None.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects (>=25%) for binimetinib, in combination with encorafenib, for the treatment of melanomainclude fatigue, nausea, diarrhea, vomiting, and abdominal pain.
The most common adverse effects (>=25%) for binimetinib, in combination with encorafenib, for the treatment of NSCLC include fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of binimetinib have not been established in pediatric patients.
Binimetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.
It is not known whether binimetinib or its metabolites are distributed into human milk. Because of the potential for serious adverse reactions to binimetinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 3 days after the last dose. The effects of the drug on nursing infants or on the production of milk are unknown.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In clinical trials evaluating binimetinib (45 mg twice daily) in combination with encorafenib (300-600 mg once daily) in patients with BRAF mutation-positive melanoma, 20% of patients were 65-74 years of age and 8% were >=75 years of age. In a clinical trial of patients with BRAF V600E mutation-positive metastatic NSCLC administered binimetinib in combination with encorafenib, 63.2% of patients were>=65 years of age and 20.4% were>=75 years of age. No overall differences in safety or efficacy were observed between geriatric patients and younger adults.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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