Selumetinib - Dosage, Mechanism of Action, Side Effects, and Warnings

Overview:

Selumetinib is used to treat neurofibromatosis, which is a genetic disorder that may cause tumors on the nerves in children of two years or more. Neurofibromatosis may cause tumors in the spinal cord or brain, which may lead to learning disabilities, bone deformities, or tumors under the skin. One kind of neurofibromatosis is plexiform neurofibromas, which are large tumors that grow from the nerves anywhere in the body and become cancerous later in life. Selumetinib is the drug that is used for children suffering from plexiform neurofibromas, which can not be surgically removed.

Warnings:

It is important to follow all the instructions properly given on the label of the drug and the instructions given by the doctor. The patient should inform the doctor about all the allergies and complications to the doctor.

Side Effects of Selumetinib:

• There can be any allergy to the drug leading to hives, difficulty in breathing, swelling in the eyes, lips and tongue, and throat.

• Some other side effects of Selumetinib include severe diarrhea, which can be regular.

• Heart problems such as fast heartbeats lead to tiredness, shortness of breath, and swelling in the lower legs.

• Vision changes may lead to blurred vision, loss of seeing dark spots, or floaters in the vision.

• Unexplained muscle pain may be tender and lead to weakness with unusual tiredness, dark-colored urine, and fever.

• Skin rashes with blistering and peeling are seen in some cases of Selumetinib.

• Diarrhea is the most common effect of the Selumetinib drug, which is observed in the patients.

What Is Neurofibromatosis?

Neurofibromatosis is a genetic disorder that causes the formation of tumors on the nerve tissue. These tumors can be formed anywhere in the nervous system, like the spinal cord and the nerves. There are three types of neurofibromatosis, namely neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. Neurofibromatosis 1 is usually diagnosed in childhood, whereas schwannomatosis and neurofibromatosis 2 are diagnosed in early adulthood. The tumors formed in this disorder are generally non-cancerous (benign), but in some rare cases, they can turn malignant in nature. The treatment of neurofibromatosis should be focused on encouraging healthy growth and development in the patient, as the children affected by this disorder need early management of the complications.

Symptoms of Neurofibromatosis:

• Neurofibromatosis 1:

The symptoms seen in patients suffering from neurofibromatosis are:

1. Flat, light brown spots on the skin.

2. Tiny bumps on the iris of the eye.

3. Soft pea-sized bumps are present either on the skin or under the skin.

4. Bone deformities.

5. Learning disabilities.

6. Short stature with below average height.

7. Larger head than average size.

8. Formation of tumor on the optic nerve.

9. Presence of tumors in armpits or the groin area.

• Neurofibromatosis 2:

It shows symptoms such as:

1. Loss of hearing which is not sudden but occurs gradually.

2. Poor body balance.

3. Frequent headaches.

4. A feeling of hearing in the ear.

5. Affects both the ears by benign tumor formation in them.

6. Facial drop.

7. Pain.

8. Vision problems or cataracts.

9. Seizures.

10. Numbness or weakness in the arms and legs of the child.

• Schwannomatosis:

The symptoms seen in children suffering from schwannomatosis are:

1. Chronic pain which can appear anywhere in the body and can lead to disability.

2. Loss of muscle.

3. Numbness or weakness in several parts of the body.

For Patients:

More About the Drug:

Before Starting the Drug:

• The most important condition to be considered while giving Selumetinib is that it should not be given to children less than two years of age.

• It is important to inform the doctor if the child is suffering from any problems such as vision issues, liver problems, or heart problems.

• A girl who has entered into her puberty age should have a negative pregnancy test done before starting Selumetinib.

• In the cases of adults, women taking Selumetinib should use effective birth control and avoid pregnancy.

• Selumetinib can harm the unborn child in cases where the mother or father is taking Selumetinib.

• Birth control should be done for at least a week more after taking the last dose of Selumetinib.

• Boys who are taking Selumetinib and have female sex partners who are trying for pregnancy should take birth control measures as the drug can affect the fetus.

• If the patient is breastfeeding, she should avoid Selumetinib for at least a month.

How to Start Selumetinib?

• All the directions given on the label of the prescription should be followed properly by the patient. The drug should be taken according to the instructions given by the doctor.

• The medicine should be taken with a full glass of water on an empty stomach at least one hour before taking any food, or else one hour or two hours after the meal.

• The medicine should be taken at the same time every day at 12 hour intervals.

• The capsule should be swallowed completely and should not be crushed, chewed, broken, or opened.

• If the patient vomits very shortly after taking Selumetinib, it is recommended to avoid another dose until its time is reached.

• It is important to inform the doctor if there is loose stool after taking Selumetinib. The doctor may prescribe anti-diarrhea drugs to control it. Plenty of liquids should be consumed in case of diarrhea.

• If the child is having difficulty swallowing the tablet, it should be informed to the doctor.

• Selumetinib can lead to less pumping of the blood than normal and the functioning of the heart should be checked every three months to six months while taking the drug.

• The doses of Selumetinib are dependent on the surface area and height of the person. The doses of drugs should be altered if the weight and body of the person change.

• Selumetinib can lead to eye problems in some cases, which may lead to eye blindness. Frequent vision exams should be carried out to avoid any such complications.

• The doses of Selumetinib should not be changed without the doctor’s instructions.

Storage of Selumetinib: The drug should be stored at room temperature and away from moisture and heat. The capsules should be kept in their original containers with the canister of moisture-absorbing preservatives.

What if a Dose of Selumetinib Is Missed?

The medicine should be taken at the right time always, but if the dose is missed, it is advised to miss the dose if there is less than six hours time left for the next dose. Two doses should not be consumed at once.

Food to Be Avoided While Taking Selumetinib: Fluids such as grapefruit should be avoided with Selumetinib as it may lead to unwanted side effects.

St. John’s wort containing herbal supplements should also be avoided.

Common Side Effects of Selumetinib:

• Nausea, vomiting, and stomach pain.

• Itching.

• Dry skin and rashes along with acne formation.

• Tiredness and weakness in the body.

• Soreness or mouth pain with swollen gums.

• Headache.

• Fever.

• Bone pain or muscle pain.

• Redness around the fingerprints.

Doses of Selumetinib:

• The dose of the drug in cases of usual pediatric fibromatosis in two years or older individuals is 12 mg/m2 taken orally twice a day for approximately 12 hours until there is disease progression or unacceptable toxicity.

• Doses depending on the surface area of the body:

  • Body surface area (BSA) less than 0.55 mg/m2 - no doses recommended.

  • Body surface area (BSA) 0.55 m2 to 0.69 m2: 20 mg/m2 is given orally in the morning and 10 mg/m2 in the evening.

  • Body surface area (BSA) 0.7 to 0.89 m2: 20 mg/m2 orally in the morning and a dose of 20 mg/m2 in the evening.

  • Body surface area 1.9 or greater: 50 mg orally in the morning and 50 mg/m2 in the evening.

For Doctors:

Indication: In several types of malignancies, the activation of Raf-MEK-ERK is implemented, thus MEK (mitogen-activated protein kinase kinase) inhibitors such as Selumetinib are some important tools that can target the problematic overactivity of this pathway. Selumetinib has shown impressive efficacy in phase 1 trials which led to a continued investigation in the treatment of various types of tumors in phase 2 trials. Selumetinib is approved solely in cases for the treatment of Neurofibromatosis type 1 in a limited age group. The use of Selumetinib in patients suffering from neurofibromatosis type 1 has shown efficacy in shrinking, which is associated with tumors and is linked to other positive clinical outcomes. Although the drug is investigated for the treatment of several malignancies, it is currently indicated only for the treatment of neurofibromatosis type 1 in patients who are two years or older.

Pharmacodynamics: Selumetinib is a non-ATP competitive mitogen-activated protein kinase kinase 1 and 2 inhibitor, which is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often considered overactive in some types of malignancies. A study about the effects of Selumetinib in children with neurofibromatosis 1 found that the treatment with the antineoplastic resulted in a reduction in the tumor size of the malignancies. It was reported that there was a decrease in tumor-associated pain and improvements in the overall function of the person.

Mechanism of Action: The Ras-Raf-MEK-ERK signaling cascade is known to activate in many cases of cancer and is responsible for the regulation of transcription of proteins involved in the process of apoptosis. It was also proposed by studies that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. The Raf-MEK-ERK pathway can be regulated by Ras as well as several kinases and phosphatases. Often in cases of cancer Ras which is a G-protein receptor, is deregulated, which allows the downstream signaling to proceed unchecked. After many complex steps, Raf phosphorylates and MEK activates, which are then able to exert their effect on many downstream targets. The therapies which help to inhibit the upstream component of this pathway are demanding targets for cancer treatment.

Selumetinib is known to exert its effect by selectively stopping MEK 1 and MEK 2, which can then effectively blunt the pleiotropic effects possessed by the Ras-Raf-MEK-ERK cascade. By inhibition of this oncogenic pathway, Selumetinib is known to reduce cell proliferation and promote pro-apoptotic signal transduction.

Absorption: According to several studies of Selumetinib at various doses in both pediatric and adult populations, the Tmax ranges between 1 hour to 1.5 hours. In healthy adults, the mean absolute value for bioavailability was reported as 62%. The drug is advised to be consumed on an empty stomach as the food can significantly decrease the concentration of the drug.

The volume of Distribution: The mean volume of distribution of the drug Selumetinib in pediatric patients is between 78 L to 171 L.

Protein Binding Capacity: Studies that investigated Selumetinib protein binding found that about 96 % of the Selumetinib was bound to serum albumin, whereas only less than 35 % was bound to alpha-1 acid glycoprotein. The overall concentration of Selumetinib, which is plasma protein bound, is 98.4 %.

Metabolism: Selumetinib is metabolized mostly in the liver, and the pathway is:

• Hydrolysis of Selumetinib’s amide functional group produces M15 which contains carboxylic acid.

• The primary amide is formed by the elimination of the ethanediol moiety from the parent compound. Amide is known to hydrolyze M14 into M15 and glucuronide and further leads to oxidation of M14, leading to M2, M6, and M1, and also leads to M2, M6, and M1. The amide glucuronide M2 is considered a major circulating metabolite.

• The demethylation of Selumetinib produces pharmacologically active M8 and then further oxidation of M8 leads to M11. M8, on glucuronidation produces M3 or M5 and then elimination of ethanol moiety from M8, which may cause primary amide.

• The M8 (N-demethylated metabolite) accounts for about less than 10 % of the circulating metabolites and can be responsible for about 21 % to 35 % of any observed pharmacological activity.

• Ribose conjugation is known to transform M12 into M9, whereas oxidation of M12 may lead to M10 and M13 metabolites. Glucuronidation of M10 produces M1.

• Direct glucuronidation of Selumetinib produces M4 or M7, with M3 and M5 metabolites.

Route of Elimination: It was observed that about 59 % of Selumetinib is eliminated in the feces while almost 33 % of it is eliminated in the urine.

Half-Life of Selumetinib: Selumetinib has a short half-life. The elimination half-life associated with a dose of 25 mg/m square in pediatric patients is 6.2 hours. In other studies, it was estimated that 75 mg is administered twice, and the half-life is reported to be approximately 13 hours.

Clearance: The clearance of Selumetinib in children is 8.8 L/hr. A study in healthy adult males found a clearance value of 15.7 L/hr.

Toxicity of Selumetinib: The information about the toxicity of Selumetinib is very limited and not readily available. Patients who are experiencing an overdose are at an increased risk of adverse effects like cardiomyopathy, ocular toxicity, and diarrhea.

Drug Interactions:

• Abemaciclib: It is a medication used to treat HR + HER2 advanced or metastatic breast cancer. It helps to decrease the excretion rate of Selumetinib, which can result in higher serum levels.

• Acetaminophen: It is an analgesic drug that is used in combination or alone with opioids for pain management or as an antipyretic agent. Selumetinib may increase the hepatotoxic activities of Acetaminophen.

• Alprazolam: It is a triazolobenzodiazepine with intermediate onset, which is commonly used in the treatment of panic disorders and generalized anxiety along with anxiety associated with depression. The metabolism of Selumetinib can be decreased when combined with Alprazolam.

• Bisoprolol: The serum concentration of Selumetinib can be increased when it is consumed with Bisoprolol. It is a beta-1 adrenergic blocking agent used to prevent myocardial infarction and heart failure and to treat mild to moderate hypertension.

Food Interactions: Selumetinib should be consumed with or without food as the absorption is unaffected by food.

Selumetinib and Pregnancy: Selumetinib should be avoided in cases of pregnancy as it can affect the unborn child. The drug is so dangerous for the fetus that even when the father consumes the drug during the pregnancy plan, it can affect the child.

Selumetinib and Breastfeeding: It is important to avoid Selumetinib at the time of breastfeeding for at least one month. The drug is dangerous for the newborn child.

Selumetinib in Geriatric Patients: Selumetinib can be given to patients who are old but should be strictly followed by the doctor’s advice. The doses should not be altered by the patient.