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General Description:

Belzutifan, identified by CAS number 1672668-24-4, is a notable compound with significant therapeutic applications. Belzutifan is an inhibitor of hypoxia-inducible factor 2α (HIF-2α) used in the treatment of von Hippel-Lindau (VHL) disease-associated cancers. The HIF-2α protein was first identified in the 1990s by researchers at UT Southwestern Medical Center as a key player in the growth of certain cancers. Initially considered to be undruggable, a binding pocket was eventually discovered in the HIF-2α molecule which allowed for compounds to bind and inhibit these proteins. This discovery led to the initial development of belzutifan (at the time called PT2977), which was further developed by a spin-off company named Peloton Pharmaceuticals (which itself was eventually acquired by Merck in 2019). Belzutifan inhibits the complexation of HIF-2α with another transcription factor, HIF-1β, a necessary step in its activation - by preventing the formation of this complex, belzutifan can slow or stop the growth of VHL-associated tumors. Belzutifan received FDA approval for the treatment of select VHL-associated cancers on August 13, 2021.

Indications:

This drug is primarily indicated for: Belzutifan is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), who do not require immediate surgery. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Belzutifan undergoes metabolic processing primarily in: Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Belzutifan are crucial for its therapeutic efficacy: In patients with VHL disease-associated renal cell carcinoma, the mean C_max and AUC_0-24h at steady-state - which was achieved after approximately three days of therapy - were 1.3 µg/mL and 16.7 μg•hr/mL, respectively. The median T_max is one to two hours following oral administration. The administration of belzutifan with food has a negligible effect on drug disposition - when given alongside a high-calorie, high-fat meal, the T_max was delayed by approximately 2 hours with no other clinically meaningful effects observed. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Belzutifan is an important consideration for its dosing schedule: The mean elimination half-life of belzutifan is 14 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Belzutifan exhibits a strong affinity for binding with plasma proteins: Plasma protein-binding is approximately 45%, although data regarding the specific proteins to which belzutifan binds are unavailable. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Volume of Distribution:

Belzutifan is distributed throughout the body with a volume of distribution of: The steady-state volume of distribution of belzutifan following oral administration is approximately 130 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Belzutifan is a critical factor in determining its safe and effective dosage: The mean clearance of belzutifan following oral administration is 7.3 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Belzutifan exerts its therapeutic effects through: Belzutifan exerts its therapeutic effects by inhibiting a transcription factor necessary for the growth of solid tumors associated with VHL disease. It is taken once daily at approximately the same time each day, with or without food. Both severe anemia and hypoxia have been observed following therapy with belzutifan, and patients should be monitored closely before and during therapy to ensure patients can be managed as clinically indicated. There are no data regarding the use of erythropoiesis-stimulating agents for the treatment of belzutifan-induced anemia, and as such these therapies should be avoided. Belzutifan may cause embryo-fetal toxicity when administered to pregnant women. Female patients and male patients with female partners of reproductive potential should ensure that an effective form of contraception is used throughout therapy and for one week after the last dose - as belzutifan appears to decrease the efficacy of systemic hormonal contraceptives, patients should be advised to use an additional method of contraception (e.g. condoms) to eliminate the possibility of pregnancy during therapy. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Belzutifan functions by: Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia. In healthy patients, when oxygen levels are normal, HIF-2α is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2α translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1β (HIF-1β) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis. Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2α, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2α that prevents its complexation with HIF-1β in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2α target genes and slowing/stopping the growth of VHL-associated tumors. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Belzutifan is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, MATE 2 Inhibitors, MATE inhibitors, OATP1B1/SLCO1B1 Substrates, OATP1B3 substrates, P-glycoprotein substrates, UGT2B17 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Belzutifan include:

• Water Solubility: Insoluble