Cobimetinib
Cobimetinib Uses, Dosage, Side Effects, Food Interaction and all others data.
Cobimetinib is an orally active, potent and highly selective small molecule inhibiting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), and central components of the RAS/RAF/MEK/ERK signal transduction pathway. It has been approved in Switzerland and the US, in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma.
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.
| Trade Name | Cobimetinib |
| Availability | Prescription only |
| Generic | Cobimetinib |
| Cobimetinib Other Names | Cobimetinib |
| Related Drugs | Keytruda, pembrolizumab, Opdivo, nivolumab, ipilimumab, Yervoy |
| Weight | 20mg |
| Type | Oral tablet |
| Formula | C21H21F3IN3O2 |
| Weight | Average: 531.318 Monoisotopic: 531.06306 |
| Protein binding | 95% bound to human plasma protein. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Cobimetinib is an antineoplastic agent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway used to treat unresectable or metastatic melanoma.
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.
Cobimetinib is also used to associated treatment for these conditions: Metastatic Melanoma, Unresectable Melanoma
How Cobimetinib works
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.
Toxicity
The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting.
Food Interaction
- Avoid grapefruit products. Grapefruit inhibits the metabolism of cobimetinib through the CYP3A4 pathway and, therefore, may increase serum levels of cobimetinib.
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of cobimetinib.
- Take with or without food. Cobimetinib bioavailability is unaffected by food.
[Moderate] MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib.
However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4.
Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.
MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib.
Grapefruit and grapefruit juice should be avoided if an interaction is suspected.
Orange juice is not expected to interact with these drugs.
Cobimetinib Drug Interaction
Major: diltiazemUnknown: charcoal, multivitamin with minerals, sulfamethoxazole / trimethoprim, ubiquinone, prochlorperazine, copper gluconate, glucose, acetazolamide, lidocaine / prilocaine topical, ethanol, glycerin, tbo-filgrastim, eribulin, heparin, sodium iodide, arginine, levocarnitine, bioflavonoids, cholecalciferol
Cobimetinib Disease Interaction
Moderate: cardiomyopathy, hepatotoxicity, ocular toxicities, rhabdomyolysis, lung toxicity
Volume of Distribution
806L in cancer patients based on a population PK analysis.
Elimination Route
The bioavailability of cobimetinib is 46%, the AUC and Cmax is unaffected by food.
Half Life
Average half life was 44 hours.
Clearance
13.9L/h
Elimination Route
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.
Innovators Monograph
You find simplified version here Cobimetinib
