Voxelotor API Manufacturers

General Description:

Voxelotor, identified by CAS number 1446321-46-5, is a notable compound with significant therapeutic applications. Voxelotor is a novel hemoglobin S polymerization inhibitor for the treatment of sickle cell disease. This is a genetically inherited condition most prevalent in the Middle East, Africa, and certain parts of India. Sickle cell disease can lead to excruciating pain, stroke, infection, and various other complications arising from the blockage of blood vessels. Voxelotor was granted accelerated FDA approval on November 25 2019, as it is likely to be a promising treatment for the 100,000 individuals in the U.S. suffering from the disease, in addition to 20 million others worldwide. It was developed by Global Blood Therapeutics, Inc. and is unique from other drugs used to treat sickle cell anemia, such as , , and due to its novel mechanism of action. The EMA approved the use of voxelotor for the treatment of hemolytic anemia associated with sickle cell disease in February 2022.

Indications:

This drug is primarily indicated for: In the US, voxelotor is indicated to treat sickle cell disease in both adult and pediatric patients aged 4 years and older. In Europe, it is indicated for the treatment of hemolytic anemia due to sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older as monotherapy or in combination with . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Voxelotor undergoes metabolic processing primarily in: Voxeletor is heavily metabolized via 2 phases. Phase I consists of oxidation and reduction, while phase II consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4, and to a lesser extent by CYP2C19, CYP2B6, and CYP2C9 hepatic cytochrome enzymes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Voxelotor are crucial for its therapeutic efficacy: Voxelotor is rapidly absorbed after oral administration, with a plasma Tmax of 2 hours. Tmax in the red blood cells ranges from 17-24 hours. The Cmax, on average in whole blood and red blood cells occur 6 and 18 hours after an oral dose, respectively. Consumption of a high fat meal with voxelotor significantly increased exposure to the drug during clinical trials. After a daily dose of either 300, 600, or 900 mg for a period of 15 days, when steady-state concentrations were reached, the average RBC Cmax for the respective doses were measured to be 4950, 9610 and 14 000 μg*h mL−1, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Voxelotor is an important consideration for its dosing schedule: The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours, according to the FDA label. The mean half-life in the red blood cell is 60 days. The average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy patients, in one clinical study. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Voxelotor exhibits a strong affinity for binding with plasma proteins: The protein binding of voxeletor is 99.8%, according to in vitro studies. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Voxelotor from the body primarily occurs through: 62.6% of the voxelotor dose administered orally as well as its metabolites are found in the feces (with 33.3% as unchanged drug) and 35.5% in urine (with only 0.08% unchanged drug). Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Voxelotor is distributed throughout the body with a volume of distribution of: The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Voxelotor is a critical factor in determining its safe and effective dosage: The apparent oral clearance of voxelotor is approximately 6.7 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Voxelotor exerts its therapeutic effects through: Voxelotor modifies hemoglobin to prevent painful and dangerous sickle cell crises that normally lead to organ damage, hospitalization, and sometimes death. It prevents low hemoglobin, which is normally associated with the destruction of sickled blood cells in sickle cell disease. Voxelotor has led to up to a 40% increase in hemoglobin in clinical trials. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Voxelotor functions by: Deoxygenated sickle hemoglobin (HbS) polymerization is the causal factor for sickle cell disease. The genetic mutation associated with this disease leads to the formation of abnormal, sickle shaped red blood cells that aggregate and block blood vessels throughout the body, causing vaso-occlusive crises. Voxelotor binds irreversibly with the N‐terminal valine of the α‐chain of hemoglobin, leading to an allosteric modification of Hb20, which increases the affinity for oxygen. Oxygenated HbS does not polymerize. By directly blocking HbS polymerization, voxelotor can successfully treat sickle cell disease by preventing the formation of abnormally shaped cells, which eventually cause lack of oxygenation and blood flow to organs. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Voxelotor belongs to the class of organic compounds known as hydroxybenzaldehydes. These are organic aromatic compounds containing a benzene ring carrying an aldehyde group and a hydroxyl group, classified under the direct parent group Hydroxybenzaldehydes. This compound is a part of the Organic compounds, falling under the Organic oxygen compounds superclass, and categorized within the Organooxygen compounds class, specifically within the Carbonyl compounds subclass.

Categories:

Voxelotor is categorized under the following therapeutic classes: Aldehydes, Blood and Blood Forming Organs, Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Hematologic Agents, Hemoglobin S Polymerization Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Voxelotor include:

• Water Solubility: insoluble in water
• Melting Point: 80-82
• Boiling Point: 539.2±50.0
• logP: 2.85
• pKa: 7.67±0.10