Belzutifan - Dosage, Benefits, and Side Effects

Overview:

A drug called Belzutifan, sometimes referred to as MK-6482, is used to treat Von Hippel-Lindau's (VHL) illness. The development of tumors and cysts in several organs, including the brain, spine, kidneys, and pancreas, is a rare hereditary condition known as VHL. Belzutifan offers a tailored therapy approach for VHL illness by blocking a particular protein implicated in the formation of malignant tumors. On August 13th, 2021 the United States Food and Drug Administration (FDA) approved Belzutifan for the management of clear cell renal cell carcinoma associated with von Hippel-Lindau (VHL) disease..

Drug Group:

Belzutifan is a medication that is a member of the hypoxia-inducible factor (HIF) inhibitors class. Von Hippel-Lindau (VHL) disease is a hereditary illness that manifests as tumors and cysts growing in different organs. It is treated with this medication. HIF inhibitors, such as Belzutifan, function by preventing hypoxia-inducible factors from growing aberrant blood vessels and tumors linked to VHL illness.

Dosages:

The recommended Belzutifan dosage is 120 mg (milligrams) taken orally once daily, either with or without food, consistently at the same time each day until disease progression or unacceptable toxicity is seen. Swallow the tablets whole. Do not chew, crush, or split them. If a dose is missed, take it as soon as possible on the same day and resume the regular schedule the next day. Do not take extra tablets to compensate for a missed dose. In case of vomiting after taking Belzutifan, do not retake the dose; continue with the next scheduled dose on the following day.

For Patients:

What Is Von Hippel-Lindau (VHL)?

An uncommon genetic condition called Von Hippel-Lindau (VHL) makes people more likely to develop several types of tumors and cysts. It is brought on by mutations in the VHL gene, which raises the possibility of kidney, eye, brain, and other organ malignancies. Frequent medical monitoring is essential for the early identification and treatment of associated concerns.

What Is the Management of Von Hippel-Lindau (VHL)?

• Regular surveillance for tumor development.

• Tumors can be surgically removed when necessary.

• Drugs for the treatment of problems and symptoms.

• Genetic advice to relatives.

• Supportive treatments for related illnesses.

• Ongoing observation and treatment modifications with each patient's needs.

How Does Belzutifan Work?

Belzutifan, sometimes referred to as MK-6482, is a medication that is a member of the HIF-2 alpha inhibitor pharmacological class. It functions by preventing the action of a protein called hypoxia-inducible factor-2 alpha (HIF-2 alpha), which is implicated in the body's reaction to low oxygen levels. Belzutifan helps to lessen the creation of specific proteins that encourage the growth of tumors in some types of malignancies, especially clear cell renal cell carcinoma (ccRCC), by inhibiting HIF-2 alpha. This specific approach aims to eventually obstruct the cancer's spread by interfering with its ability to adapt to low-oxygen surroundings.

How Should the Drug Be Taken?

Belzutifan is recommended at a daily dosage of 120 mg, taken orally. It should be taken consistently at the same time each day, with or without food. Swallow the tablets whole, and do not chew, crush, or split them. If a dose is missed, take it as soon as possible on the same day and resume the regular schedule the next day. In case of vomiting after taking Belzutifan, do not retake the dose and wait until the next day.

What Are the Benefits of Using Belzutifan for Von Hippel-Lindau (VHL) Disease?

• Tumor Size Reduction: Studies including Belzutifan have demonstrated efficacy in decreasing the size of tumors linked to Von Hippel-Lindau (VHL) illness.

• Disease Stabilization: It aids in slowing the growth of tumors connected to VHL, possibly averting more problems.

• Improvement in Symptoms: Because of the beneficial effect on tumor growth, patients may feel relief from the symptoms associated with VHL disease.

• Possibility of Avoiding Surgery: In certain situations, Belzutifan may be able to avoid surgery by efficiently controlling the size of the tumor.

• Oral Administration: Patients have a convenient and non-invasive therapy alternative with this medication's oral version.

What Must the Patient Inform the Doctor Before Taking Belzutifan?

Patients should discuss their medical history with their doctor before using Belzutifan, particularly if they have a history of bleeding disorders, high blood pressure, liver or kidney issues, or any other medical condition. To prevent any potential problems, patients should also reveal all of the drugs, vitamins, and herbal products they are currently using. To guarantee that Belzutifan is used safely and effectively, the physician must have a thorough awareness of the patient's medical condition.

What Are the Side Effects of Using Belzutifan?

• Fatigue.

• Anemia.

• Hypertension.

• Nausea.

• Vomiting.

• Decreased appetite.

• Joint pain.

• Headache.

• Dyspnea (difficulty breathing).

• Cough.

For Doctors:

Description:

Belzutifan, an inhibitor of hypoxia-inducible factor-2α (HIF-2α), has the chemical name 3­[[(1S,2S,3R)-2,3-Difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5­fluorobenzonitrile. It is a white to light brown powder with a molecular formula of C17H12F3NO4S and a molecular weight of 383.34 Daltons. The compound exhibits solubility in acetonitrile, dimethoxyethane, and acetone, is sparingly soluble in ethyl acetate, very slightly soluble in isopropanol and toluene, and remains insoluble in water. Belzutifan comes in the form of blue, film-coated tablets designed for oral consumption, each containing 40 mg of Belzutifan. The tablets consist of various inactive ingredients such as croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and silicon dioxide.

Therapeutic Uses of Belzutifan:

• Belzutifan, also known as MK-6482, is a hypoxia-inducible factor prolyl hydroxylase inhibitor.

• Used in the treatment of clear cell renal cell carcinoma (ccRCC), a type of kidney cancer.

• It acts by stabilizing hypoxia-inducible factor-2 alpha (HIF-2α), leading to reduced tumor growth. It can be prescribed for patients who are not candidates for surgery or systemic therapies.

• It may offer an alternative for those with advanced or metastatic ccRCC.

Dosage Forms and Strengths:

40 mg blue oval-shaped tablets with film coating that are plain on one side and embossed with "177" on the other.

Dosage and Administration:

The recommended dosage for Belzutifan is 120 mg once daily until disease progression or unacceptable toxicity. Take it at the same time daily, with or without food. Swallow the tablets whole; do not chew, crush, or split. If a dose is missed, take it as soon as possible on the same day; resume the regular schedule the next day. Do not take extra tablets to compensate for a missed dose. If vomiting occurs, do not retake the dose and take the next dose the following day. Dosage reductions for adverse reactions are with the first reduction to 80 mg and the second to 40 mg. A third reduction results in permanent discontinuation.

Indications:

Belzutifan is a drug that is used to treat some kinds of cancer, particularly renal cell carcinoma (RCC), which is a kind of cancer that is related to Von Hippel-Lindau (VHL) disease. Treating people with this particular type of renal cell carcinoma linked to VHL illness is the primary use of Belzutifan. It functions by blocking a certain enzyme that is necessary for the development of blood vessels, which aids in the reduction or slowing of tumor growth.

Contraindications:

If Belizutifan is given to pregnant women, it may be harmful to the growing fetus. Belzutifan appears to impair fertility. Hence, it is imperative that both female patients and male patients who have female partners who can conceive utilize effective contraception during treatment and for one week following the last dosage.

Warnings and Precautions:

Belzutifan may lead to severe anemia. This was observed in 90 percent of patients in studies, with seven percent experiencing Grade 3 anemia. Anemia onset typically occurs around thirty-one days. In another trial, anemia affected 76 percent of patients, with 28 percent experiencing Grade 3 anemia. Monitoring for anemia is crucial, especially in dual UGT2B17 and CYP2C19 poor metabolizers. A blood transfusion may be necessary, and for hemoglobin less than 9 g/dL(grams per deciliter), Belzutifan should be withheld until levels improve. The use of erythropoiesis-stimulating agents (ESAs) is not recommended due to unknown safety and effectiveness. Additionally, Belzutifan may cause severe hypoxia, noted in 1.6 percent of patients in one study and 29 percent in another study. Oxygen saturation should be monitored before and during treatment, and if decreased saturation occurs, consider withholding Belzutifan until resolved.

What Are the Adverse Reactions of Belzutifan?

• Hypertension.

• Dyspnea (difficulty breathing).

• Cough.

• Rash.

• Decreased appetite.

• Headache.

• Vomiting.

Pharmacological Aspects of Belzutifan

• Mechanism of Action:

Belzutifan inhibits hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor pivotal in oxygen sensing and the regulation of genes for hypoxia adaptation. Normally, VHL protein targets HIF-2α for degradation under sufficient oxygen levels. In the absence of functional VHL, HIF-2α stabilizes and accumulates, translocating into the nucleus to form a complex with HIF-1β (beta). This complex triggers the expression of genes linked to cellular proliferation, angiogenesis, and tumor growth. Belzutifan binds to HIF-2α, blocking its interaction with HIF-1β during hypoxia or VHL dysfunction, leading to diminished transcription and expression of HIF-2α target genes. In vivo, Belzutifan exhibits anti-tumor activity in renal cell carcinoma mouse xenograft models.

• Pharmacodynamics:

Plasma erythropoietin (EPO) levels exhibited dose- and exposure-dependent reductions up to 120 mg once daily. The most significant EPO suppression, approximately 60 percent from baseline, occurred after 2 weeks of consecutive Belzutifan dosing, with levels returning to baseline after 12 weeks. Higher Belzutifan exposure correlated with an increased incidence of Grade 3 anemia in patients with baseline hemoglobin levels <12 mg/dL. Belzutifan, at the recommended dosage, does not cause substantial QT interval increases (>20 milliseconds) in cardiac electrophysiology.

• Pharmacokinetics:

In individuals with VHL disease-associated RCC, the average steady-state Cmax is 1.3 μg/mL (42 percent), and AUC0-24h is 16.7 µg•hr/mL (52 percent), achieved after about 3 days. Both Cmax and AUC (concentration maximum and area under the curve) show how proportional increases within a dose range of 20 mg to 120 mg. Absorption peaks at a median Tmax ( time to peak drug concentration) of one to two hours, with a high-fat meal causing a two-hour delay in peak Belzutifan concentration but no significant impact on Cmax or AUC. The steady-state volume of distribution is 130 Liters (35 percent), with 45 percent plasma protein binding. Belzutifan undergoes primary metabolism by genes, with a lesser contribution from CYP3A4. Clearance is at a mean rate of 7.3 L/hr liters per hour (51 percent), and the elimination half-life is 14 hrs.

Drug Interactions:

• Calcium and vitamin D.

• Chlorpheniramine and Dextromethorphan.

• Diltiazem.

• Nirmatrelvir and Ritonavir.

• Clopidogrel.

• Acetaminophen.

• Alprazolam.

Use in Specific Populations:

• Pregnancy: Belzutifan poses a risk of fetal harm in pregnant women based on animal studies. Limited data on its use in pregnant women are available, but in animal reproduction studies, Belzutifan caused embryo-fetal lethality and skeletal malformations at exposures greater than 0.2 times the human exposure at the recommended dose. Pregnant women and those of reproductive potential should be informed about the potential fetal risks. The background risk of birth defects and miscarriage in the indicated population is unknown, with general population estimates at two to four percent and 15 to 20 percent, respectively.

• Lactation: It is recommended that women avoid breastfeeding while undergoing Belzutifan treatment and for one week after the final dose due to the lack of data on the presence and effects of Belzutifan or its metabolites in human milk. This precaution prevents potentially serious adverse reactions in the breastfed child.

• Pediatrics: The safety and effectiveness of Belzutifan have not been established in pediatric patients.

• Geriatrics: 3.3 percent of patients receiving Belzutifan were greater than 65 years old, and clinical trials did not include sufficient numbers of patients aged 65 and older to determine differences in response compared to younger patients.

• Renal Impairment: No dosage modification is recommended for Belzutifan in mild to moderate renal impairment. However, Belzutifan has not been studied in patients with severe renal impairment.

• Hepatic Impairment: Similarly, no dosage modification is recommended in mild hepatic impairment, but there is no study data for moderate or severe hepatic impairment.

Clinical Studies:

Belzutifan, an FDA-approved hypoxia inducible factor 2-alpha inhibitor in 2021 for renal cell carcinoma (RCC) in Von-Hippel Lindau (VHL) disease patients, was studied in our institution for its efficacy and adverse effects on central nervous system (CNS) hemangioblastomas (HBs). Seven VHL patients with 25 HBs received a daily 120 mg Belzutifan dose for a median of 13 months. Results showed a 71 percent objective response rate (ORR), with a median time-to-response (TTR) of five months. While no complete responses occurred, 71.4 percent showed partial response, and 28.5 percent had stable disease. Adverse events included decreased hemoglobin, fatigue, and dizziness, without severe anemia. Belzutifan seems effective and safe for CNS HBs in VHL; however, long-term effectiveness requires further clinical trials.