Eflornithine for Neuroblastoma

Overview:

Eflornithine is a drug primarily used to manage hirsutism with abnormal and excessive hair growth and trypanosomiasis (parasitic infection). However, recently, this drug has been approved to prevent or reduce the risk of relapse of a cancerous condition called neuroblastoma (tumor originating from immature nerve cells) in children and adults. Eflornithine is said to exhibit this property by inhibiting the ornithine decarboxylase enzyme. The enzyme ornithine decarboxylase is involved in the urea cycle and plays a vital role in DNA stabilization and the growth and division of cells in the body. In neuroblastoma, there is excessive and uncontrolled growth of cells. To disrupt this process, Eflornithine is employed. This drug was approved to prevent the relapse of neuroblastoma on December 13, 2023, by the US Food and Drug Administration.

Indications:

• Eflornithine is used topically as a cream to manage and treat unrestricted unwanted hair growth in the facial region in women (Hirsutism).

• Eflornithine also treats a parasitic infection called trypanosomiasis (sleeping sickness). Thus, it acts as an antiprotozoal drug.

• Eflornithine has the potential to inhibit an important enzyme, ornithine decarboxylase responsible for cell growth. The inhibition leads to the death of cancer cells. Hence, it is exclusively used to prevent the relapse of neuroblastoma. It is used in individuals with high-risk neuroblastoma who have also demonstrated excellent and effective responses against other chemotherapeutic and immunotherapeutic agents.

Contraindications:

• Hypersensitivity is exhibited by some individuals on applying Eflornithine.

• Systemic administration of Eflornithine is generally contraindicated in patients with any kind of liver disorder.

• Eflornithine is contraindicated to use in individuals with ear infections and bone marrow suppression.

For Patients:

What Is Neuroblastoma?

Neuroblastoma is a tumor that develops from immature or undeveloped neuroblasts (Nerve Cells). Generally, in healthy individuals, neuroblasts are precursor cells that develop and mature to form nervous system neurons. Neuroblasts are also responsible for the formation of adrenal medullary cells. Such matured neuroblast cells help transmit signals in the nervous system, control the body's response to external stimuli, and perform involuntary or reflex activities.

When this entire process of development and maturation is hindered, there can be excessive and uninterrupted growth of immature cells, thus causing a tumor called neuroblastoma. Genetic variations, mutations, or environmental toxin exposure are considered to be the causative agents for neuroblastoma. It is a common tumor among kids. This tumor is often seen above the kidneys (in the region of adrenal glands). Other sites where neuroblastoma occurs are the abdomen, pelvis, or neck.

What Are the Symptoms of Neuroblastoma?

• Swelling in the abdominal region is the first symptom seen.

• Pain in the abdomen and surrounding regions like the chest and the bones.

• Constipation.

• Changes in frequency of urination.

• Weight loss (sudden and unexpected).

• Appetite loss.

• Bulging of eyes (proptosis).

• Pain in the hip and leg region, especially within the bones.

• Fever.

Why Is Eflornithine Prescribed for Neuroblastoma?

Eflornithine is a drug that can irreversibly mitigate the action of ornithine decarboxylase enzymes. This enzyme is highly needed for cell growth and development. In neuroblastoma, where the number of cancer cells goes overboard due to uninterrupted cell growth and division, Eflornithine's mechanism of action in inhibiting the ornithine decarboxylase enzyme becomes relevant. By disrupting the activity of this enzyme, Eflornithine interferes with the rapid and uncontrolled multiplication of neuroblastoma cells. This interference in cell growth may slow down or impede tumor progression.

Also, the use of Eflornithine is indicated only in individuals with high-risk neuroblastoma (tumors with large size and widespread throughout the body to other organs) who have responded well to the chemotherapeutic treatment. Generally, high-risk neuroblastoma is treated with a combination of surgical modalities, chemotherapy, and immunotherapeutic agents like Dinutuximab, Nivolumab, and Chimeric Antigen Receptor (CAR) T-cell therapy. Only when individuals have shown adequate response to this kind of therapy will Eflornithine be prescribed to mitigate the risk of relapse.

What Are the Side Effects of Taking Eflornithine?

Infections as there is a significant compromise in the action of the immune system. Common infections seen are:

• Upper respiratory tract infection.

• Pneumonia (inflamed air sacs of the lung).

• Sinusitis (inflammation of sinuses).

• Conjunctivitis (inflamed conjunctiva).

• Otitis media.

• Urinary tract infection.

• Vaginal infections.

• Infection of the skin.

Other notable adverse effects of taking Eflornithine are:

• Diarrhea.

• Vomiting.

• The sensation of vomiting (nausea).

• Cough (persistent).

• Allergic rhinitis (sneezing with runny nose as a response to allergic substances).

• Alopecia (Hair loss).

• Rashes.

• Loss of hearing.

• Reduced lymphocyte count.

• Reduced erythrocyte count manifesting as pale skin, brittle and soft nails, and loss of taste sensation with burning sensation in the mouth.

• Reduced thrombocyte count. This causes bleeding, which can be uncontrolled. Petechiae or bleeding spots can be seen in various regions of the skin.

• Liver dysfunction. This can cause itchy skin and pale-looking stools. This can be seen through hematological examinations and liver function tests. Such tests reveal abnormalities in the levels of alanine transaminase and aspartate transaminase.

How Should Eflornithine Be Taken for Treating Neuroblastoma?

Eflornithine will be given as a tablet with dosage depending on the body surface area of the patients. Eflornithine should be taken twice a day. It can be swallowed whole or crushed and mixed with liquid to facilitate deglutition. If the drug is mixed with liquid for ease of consumption, the entire mixture should be consumed within an hour and should not be kept stagnant or exposed for more than one hour.

The storage temperature of the drug Eflornithine should be around 68 to 77 degrees Fahrenheit (20 to 25 degrees Celsius). The entire course of treatment with Eflornithine is two years.

In any case, where a specific dose of Eflornithine is missed, it can be taken immediately. However, if the next dosage schedule is within seven hours, patients should skip that particular dose and proceed with the subsequent doses and schedule.

What Are the Precautionary Measures to Be Taken Before Taking Eflornithine?

• As mentioned above, hearing loss is an important adverse effect of taking Eflornithine. So, an audiogram should be performed before taking this drug to prevent any kind of loss of hearing.

• Liver function tests should be done to monitor the variations in the liver enzymes.

• Any kind of medications taken by the patient should be informed to the doctor as there can be interaction between the drugs. This also includes herbal or traditional medicines.

For Doctors:

Clinical Pharmacology:

Eflornithine interrupts the synthesis of ornithine decarboxylase, which is responsible for regulating polyamine synthesis. This process is necessary for cell growth and proliferation. By inhibiting such an important rate-limiting enzyme, Eflornithine disrupts the conversion of ornithine to putrescine, a key step in synthesizing polyamines essential for cell division. This mechanism underlies its primary use in topical formulations to reduce unwanted facial hair growth. In the context of cancer treatment, particularly in neuroblastoma, Eflornithine's inhibition of ornithine decarboxylase activity shows promise in impeding the uncontrolled growth of cancer cells by suppressing polyamine synthesis.

Ingredients:

Active Ingredient: Eflornithine hydrochloride (A single tablet has a dosage of 192 mg (milligrams), equal to about 250 mg of Eflornithine hydrochloride).

Inactive Ingredients:

• Silicified microcrystalline cellulose - 220 mg.

• Maize starch - 25 mg.

• Silicon dioxide (Colloidal form) - 2.5 mg.

• Magnesium stearate - 2.5 mg.

Dosage and Route of Administration:

Depending on the body surface area of the individual with neuroblastoma, the dosage of Eflornithine varies. Each tablet contains 192 mg of Eflornithine.

• A single tablet is sufficient if the patient has a body surface area in the range of 0.25 to less than 0.5 square meters.

• A body surface area of 0.5 to 0.75 necessitates the intake of two tablets, equivalent to 384 mg.

• If the range of body surface area is between 0.75 to 1.5, three tablets should be prescribed (576 mg).

• Four tablets are necessary when the range goes beyond 1.5 square meters (768 mg).

Irrespective of the number of tablets, Eflornithine should be consumed orally twice a day. This regimen should be continued for two years. Every three months, the body surface area should be re-measured and changes to the dosing should be done, if necessary. In case of any adverse events following the administration of Eflornithine, the dosage should be modified accordingly.

Eflornithine is generally prescribed for patients with high-risk neuroblastoma to mitigate the risk of incidence and relapse. It is given to people who have responded well to other multimodal therapies.

Half-life:

The half-life of Eflornithine is around 3.5 hours.

Pharmacokinetics:

Absorption:

A small percentage of Eflornithine is absorbed from the gastrointestinal tract as the drug is said to have low bioavailability.

Metabolism:

Eflornithine is primarily metabolized via the process of amino acid degradation. The main metabolic pathway involves decarboxylation, where eflornithine is converted to a metabolite called difluoromethylornithine. This conversion occurs primarily through hepatic and renal routes, leading to the formation of difluoromethylornithine. This metabolite exhibits reduced polyamine synthesis due to its inhibitory action on ornithine decarboxylase.

Distribution:

After systemic administration, Eflornithine is absorbed into the circulatory system and it reaches important organs like the kidney, liver, and skin. It has very low penetrative potential through the blood-brain barrier. Hence, it does not reach the nervous system effectively.

Excretion:

Through the renal route, 90 percent of the drug (Eflornithine) and the metabolites are excreted.

Pharmacodynamics:

In neuroblastoma, the uncontrolled or uninhibited proliferation of cancerous cells is a key feature. Eflornithine's mechanism of action involves its ability to irreversibly inhibit ornithine decarboxylase, thereby disrupting the synthesis of polyamines, vital for tumor cell division. By blocking this enzymatic pathway, eflornithine interferes with the production of polyamines, ultimately suppressing the rapid and uncontrolled growth of neuroblastoma cells.

Clinical Toxicity:

• Myelosuppression is a significant adverse event associated with Eflornithine intake. So, the bone marrow is greatly reduced. As a result, all the precursor blood cells are produced in lesser amounts. This can result in low blood count, like thrombocytopenia (low platelets), lymphopenia (low lymphocytes), and anemia (low erythrocytes).

• When all such blood cells are low in circulating blood, major changes in the body occur. Some changes include blood oozing even with minimal injury, an infectious state as the immune function is compromised, and pale skin.

• Common infections seen in patients administered with Eflornithine are otitis media, upper respiratory tract infection, and sinusitis.

• Liver dysfunction (hepatotoxicity) is noted. This can be seen as increased enzyme levels of alanine aminotransferase and aspartate aminotransferase.

• Consistent ear infections can lead to hearing loss in some cases. The hearing loss can go up to grade three or four. (Severe or profound loss of hearing that can lead to deafness).

In case of these adverse reactions, especially when blood cell counts like neutrophils are less than 50 cells/cu.mm, platelets less than 25,000 cells/cu.mm, or hemoglobin levels below 8g/dL are noticed, and the drug dosage should be reduced immediately. The dosage of the drug should be reduced by one level. For individuals taking only 192 mg tablets, the frequency should be reduced from twice to once daily.

All such dose monitoring and adjustments can be done only when the patients are periodically subjected to hematological investigations, blood smear examinations, audiograms, and liver function tests.

Guidelines for Specific Population:

• Pregnant and Lactating Population:

Eflornithine is contraindicated for pregnant ladies as it can cause harm to the growing fetus. It can also lead to the death of the fetus. Females should be advised to use proper methods of contraception during the entire course of treatment (two years) and at least one week after the last dose of Eflornithine. Eflornithine is also not indicated for lactating people. However, there are no extensive studies on the presence of excretion of Eflornithine into breast milk.

• Males:

Males should also be advised to use contraceptive methods effectively till the end of the course regimen with Eflornithine and one week after the completion of the therapy.

• Pediatric Population:

Eflornithine prevents the recurrence of high-risk neuroblastoma in the pediatric population. Extensive research and studies are required to titrate the dosing for pediatric and adult populations.

Overall, Eflornithine has emerged as a drug of interest for oncological purposes other than the potential to treat facial hirsutism. This has become a breakthrough as such advances can increase the life span, especially in the pediatric population. Further research and clinical trials are essential to ascertain its optimal use, effectiveness, and safety in managing neuroblastoma and other malignancies.