}

Belzutifan

Chemotherapies

Drug Overview

Belzutifan (brand name Welireg) is a first-in-class small-molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α). It was approved by the FDA for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma and other tumors.

Belzutifan is indicated for patients with VHL disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors. It offers a non-surgical systemic option for these rare, inherited tumors.

The mechanism of action involves selective binding to HIF-2α, preventing its dimerization with HIF-1β. This disrupts downstream hypoxia signaling, reduces transcription of erythropoietin and angiogenic factors, and inhibits tumor growth.

Relevant Genes and Their Roles

Belzutifan is primarily metabolized by the cytochrome P450 enzyme CYP2C19, which oxidizes the drug in the liver to more water-soluble metabolites for elimination. CYP2C19 activity can vary widely between individuals based on genetic variants.

Genetic variations in CYP2C19 can alter the rate of belzutifan clearance. Patients with reduced-function alleles may have slower drug metabolism and higher blood concentrations, while those with increased-function alleles may clear the drug more quickly. These terms (e.g., “metabolizer”) refer to how effectively an individual’s enzyme processes certain medications.

Impact of Genetics on Drug Response

CYP2C19 metabolizer phenotypes influence belzutifan exposure: poor and likely poor metabolizers may experience higher drug levels and increased risk of adverse reactions, while ultrarapid and rapid metabolizers clear the drug normally, showing no change in dosing requirements according to current FDA guidance.

Expected Clinical Effects of Genetic Variation

Ultrarapid and Rapid Metabolizer

  • Effect: Normal drug levels
  • Clinical consequence: Standard efficacy and safety profile
  • Side effects: Typical adverse events as seen in the general population (e.g., fatigue, nausea), generally mild and infrequent

Normal Metabolizer

  • Effect: Normal drug levels
  • Clinical consequence: Expected therapeutic benefit without dose adjustment
  • Side effects: Standard safety profile (mild to moderate; fatigue, headache)

Intermediate Metabolizer (including Likely Intermediate)

  • Effect: Normal drug levels
  • Clinical consequence: No dose adjustment required per FDA guidance
  • Side effects: Similar to normal metabolizers, mild and manageable

Poor Metabolizer (including Likely Poor)

  • Effect: Higher systemic concentrations
  • Clinical consequence: Increased risk of adverse reactions (anemia, hypoxia)
  • Side effects: Moderate to severe events (anemia, hypoxia); monitor closely for signs of toxicity

Indeterminate/Not Available

  • Effect: Unknown
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
  • Side effects: As per normal metabolizer until genotype is resolved

Dosing Guidelines

The following dosing guidelines are based on the available FDA recommendations for belzutifan and CYP2C19.

CYP2C19 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer No FDA guidance for this phenotype Initiate standard starting dose
Rapid Metabolizer No FDA guidance for this phenotype Initiate standard starting dose
Normal Metabolizer No FDA guidance for this phenotype Initiate standard starting dose
Intermediate Metabolizer No FDA guidance for this phenotype Initiate standard starting dose
Likely Intermediate Metabolizer No FDA guidance for this phenotype Initiate standard starting dose
Poor Metabolizer Higher systemic concentrations and increased risk of adverse reactions (anemia, hypoxia) Monitor patients for signs of toxicity; consider more frequent clinical assessments
Likely Poor Metabolizer Higher systemic concentrations and increased risk of adverse reactions (anemia, hypoxia) Monitor patients for signs of toxicity; consider more frequent clinical assessments
Indeterminate No FDA guidance for this phenotype Initiate standard starting dose
Not available No FDA guidance for this phenotype Initiate standard starting dose

Alternative Treatment Options

The FDA table does not specify alternate drugs or dosing strategies for belzutifan based on CYP2C19 genotype. Clinicians may consider standard supportive care or other systemic therapies for VHL-associated tumors if belzutifan is not tolerated.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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