selumetinib

Action and Spectrum

Actions and Spectrum: 

Actions: 

The main action of selumetinib is to inhibit the activity of MEK1, which in turn leads to the inhibition of downstream signaling through the ERK pathway. It results in a reduction in cell proliferation and an increase in apoptosis (programmed cell death) in cancer cells. selumetinib has also been shown to have anti-angiogenic effects, meaning it can inhibit the growth of new blood vessels necessary for tumor growth and spread. 

Spectrum: 

In terms of its spectrum, selumetinib has shown efficacy in several types of cancer. The FDA has approved it for treating advanced or metastatic uveal melanoma with a specific genetic mutation. It has also shown promising results in clinical trials for treating other types of cancer, such as non-small cell lung cancer and neurofibromatosis type 1. However, selumetinib is ineffective in all patients and may cause side effects such as skin rash, diarrhea, and visual disturbances. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Vomiting  

Rash  

Increased CPK  

Abdominal pain  

Diarrhea  

Nausea  

Dry skin  

Musculoskeletal pain  

Fatigue  

Pyrexia  

Decreased albumin  

Acneiform rash  

Stomatitis 

Paronychia  

Headache  

Pruritus  

Increased AST  

Decreased hemoglobin  

Dermatitis  

Increased ALT  

Constipation  

Decreased neutrophils  

Increased lipase  

Hair changes  

Epistaxis  

Hematuria  

Proteinuria  

Decreased appetite 

Decreased ejection fraction  

Sinus tachycardia  

Skin infection  

Edema  

Decreased lymphocytes  

Visual impairment  

Dry mouth  

Facial edema 

Increased weight  

Acute kidney injury  

Dyspnea  

Hypertension  

Increased alkaline phosphatase  

Increased amylase  

Decreased potassium  

Increased sodium  

Decreased sodium  

1-10% 

Pyrexia  

Increased CPK  

Rash  

Vomiting  

Paronychia  

Increased lipase  

Increased ALT  

Rash acneiform  

Dermatitis  

Increased potassium  

Decreased hemoglobin  

Decreased neutrophils  

Decreased lymphocytes  

Increased ALT  

Headache  

Hematuria  

Skin infection  

Nausea  

Decreased potassium

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

• Hypersensitivity: selumetinib should not be used in patients with known hypersensitivity to it or any of its components. 
• Pregnancy and breastfeeding: selumetinib can harm the developing fetus and may be transferred to breast milk. Therefore, it should not be used during pregnancy or breastfeeding unless the potential benefits outweigh the risks. 
• Liver and kidney disease: selumetinib is metabolized and excreted by the liver and kidneys. Patients with severe liver or kidney disease may experience decreased drug clearance and need dose adjustments. 
• Cardiovascular disease: selumetinib can cause cardiac toxicity, including prolongation of the QT interval, which can lead to severe arrhythmias. Therefore, it should be used with caution in patients with a history of cardiovascular disease or those taking medications that can prolong the QT interval. 
• Eye disorders: selumetinib can cause visual disturbances, including blurred vision, photophobia, and dry eyes. Patients with pre-existing eye disorders may be at an increased risk of developing these side effects. 
• Endocrine disorders: selumetinib can cause changes in thyroid function, including decreased levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4). Therefore, thyroid function should be monitored regularly in patients taking selumetinib. 

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus.  

Breastfeeding warnings: No data on the excretion of selumetinib in breast milk is available. Because of possible serious effects, women are advised to breastfeed one week after the last dose of selumetinib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology:  

Pharmacodynamics: 

Pharmacokinetics: 

Absorption 

Oral bioavailability for adults is 62% 

The peak plasma distribution for pediatric patients is 731 ng/mL (1st dose); 783 ng/mL (for steady state) 

The peak-plasma time for pediatric patients is 1-1.5 hours at steady-state 

The area under the curve (for pediatric patients) is 2000 ng⋅hr/mL (for 1st dose) and 1958 ng⋅hr/mL at steady state 

Distribution 

The volume of distribution is (steady-state in pediatric patients): 78 L (20 mg/m2); 171 L (30 mg/m2) 

Protein-bound is 98% 

Metabolism 

Primarily metabolized by CYP3A4 and secondarily by CYP2C19, CYP2C9, CYP2E1, CYP1A2, and CYP3A5 

Undergoes glucuronidation by UGT1A3 and UGT1A1  

Elimination and Excretion 

The rate of oral clearance is 8.8 L/hr (for pediatric patients) 

The half-life for pediatric patients is 6.2 hours (25 mg/m2) 

The drug is excreted 59% in feces and 33% in urine

Adminstartion

Administration: 

selumetinib is available in capsule form for oral administration. The capsules should be taken on an empty stomach, at least one hour before or two hours after a meal. The recommended dose of selumetinib varies depending on the indication and the patient’s characteristics, such as body weight and tolerability. 

It is essential to take selumetinib precisely as a healthcare provider prescribes and consult them before adjusting or stopping it. If a dose is missed, it should be taken as soon as possible unless it is close to the time for the next scheduled dose, in which case the missed dose should be skipped. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: selumetinib (Rx) 

Pronounced: SEL-ue-MET-i-nib 

Why do we use selumetinib? 

selumetinib is primarily used as a cancer treatment. Specifically, it is a small molecule inhibitor of MEK1/2, an enzyme part of the mitogen-activated protein kinase (MAPK) signaling pathway. This pathway is essential for cell proliferation and survival and is often dysregulated in cancer cells. 

By inhibiting MEK1/2, selumetinib blocks the downstream signaling of the MAPK pathway, leading to a decrease in cell proliferation and an increase in apoptosis (programmed cell death). selumetinib is effective in preclinical studies and clinical trials against various types of cancer, including melanoma, non-small cell lung, and thyroid cancer. 

By inhibiting MEK1/2, selumetinib blocks the downstream signaling of the MAPK pathway, leading to a decrease in cell proliferation and an increase in apoptosis (programmed cell death). selumetinib has been shown to be effective in preclinical studies and clinical trials against various types of cancer, including melanoma, non-small cell lung cancer, and thyroid cancer. 

In addition to its cancer-fighting properties, selumetinib has also been studied for its potential use in other conditions, such as neurofibromatosis type 1 (NF1) and uveitis. In NF1, selumetinib has been shown to shrink plexiform neurofibromas, benign tumors that can be disfiguring and cause other health problems. In uveitis, selumetinib has been shown to reduce inflammation in the eye.