Red blood cell (RBC) sickling is prevented by voxelotor (GBT440), which binds to the N-terminal hemoglobin (Hb) chain and increases hemoglobin S's (HbS's) affinity for oxygen [1]. It also delays HbS polymerization in vitro.

Voxelotor (GBT440; 100–150 mg/kg; given twice daily by oral gavage for 9–12 days) prolongs the half-life of red blood cells (RBCs) and decreases isolated sickle cell [1]. In mice (70 mg/kg; IV), rats (1.6 mg/kg; IV), dogs (1 mg/kg; IV), and momkeys (1 mg/kg; IV), voxelotor revealed T1/2 values of 11.7, 19.1±1.5, 66.0±11, and 28.8±4.0 hours, respectively [1]. For mice (30 mg/kg; po), rats (7.2 mg/kg; po), dogs (2.5 mg/kg; po), and momkeys (4.25 mg/kg; po), voxelotor has Cmaxs of 81.9, 71.2±6.0, 5.56±1.6, and 25.2±5.5 μg/mL[1].

Animal/Disease Models: HbSS Townes knock-in sickle mice (SS mice)[1]
Doses: 100 and 150 mg/kg
Route of Administration: Oral administration; twice a day; for 9-12 days
Experimental Results: decreased haemolysis.

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Animal/Disease Models: C57BL/6J mice, SD (Sprague-Dawley) rats, Beagle dogs and Cynomolgus monkeys[1]
Doses: 70, 1.6, 1 and 1 mg/kg for mice, rats, dogs and monkeys, respectively 30, 7.2, 2.5 and 4.25 mg/kg for mice, rats, dogs and monkeys, respectively
Route of Administration: intravenous (iv) (IV: 70, 1 6, 1 and 1 mg/kg, respectively) Oral (PO: 30, 7 2, 2 5 and 4 3 mg/kg, respectively)
Experimental Results: T1 /2s of 11.7, 19.1±1.5, 66.0±11, 28.8±4.0 hrs (hours) for mouse (70 mg/kg; iv), rat (1.6 mg/kg; iv), dog (1 mg/kg; iv), and momkey (1 mg/kg; iv), respectively. Cmaxs of 81.9, 71.2±6.0, 5.56±1.6, and 25.2±5.5 μg/mL for mouse (30 mg/kg; po), rat (7.2 mg/kg; po) , dog (2.5 mg/kg; po), and momkey (4.25 mg/kg; po), respectively.

Absorption, Distribution and Excretion
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 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.
About 62.6% of the oral dose is found in the feces, of which 33.3% is an unchanged drug. About 35.5% of the dose is recovered in urine, with only 0.08% as the unchanged drug.
The apparent volume of distribution of voxelotor in the central compartment is 338L and 72.2L in the plasma.
The apparent oral clearance of voxelotor is approximately 6.7 L/h.

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Metabolism / Metabolites
Voxeletor is heavily metabolized via two phases. Phase I metabolism consists of oxidation and reduction, while phase II metabolism consists of glucuronidation. Voseletor is oxidized mainly by CYP3A4 and by CYP2C19, CYP2B6, and CYP2C9, to a lesser extent.

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Biological Half-Life
The plasma elimination half-life of voxelotor in sickle cell disease patients is about 35.5 hours. The mean half-life in the red blood cell is 60 days. In one study, the average plasma half-life of voxelotor was 50 hours in patients with sickle cell disease, compared with 61–85 hours in healthy subjects.

Hepatotoxicity
In clinical trials of voxelotor in patients with sickle cell disease, serum aminotransferase elevations occurred in 1% to 2% of patients during therapy, but the elevations were usually asymptomatic, self-limited in course and mild-to-moderate in degree. Patients with sickle cell disease frequently have liver test abnormalities and most have some degree of jaundice, due largely to hemolysis. They are also at risk for gall stone disease (from chronic hemolysis), chronic hepatitis B and C (from blood transfusions), iron overload (from frequent transfusions), congestive liver disease (due to pulmonary hypertension), and veno-occlusive crises involving the liver which can be associated with serum aminotransferase elevations. In preregistration trials of voxelotor, hepatic events were no more common with the active drug than with placebo. Rare instances of acute aminotransferase elevations of unknown cause occurred in patients receiving voxelotor, but were self-limited in course and were not associated with worsening of preexisting bilirubin elevations or need for dose modification or discontinuation.
Likelihood score: E* (unproven but possible cause of acute liver injury with jaundice).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Voxelotor is an orally administered drug that binds to hemoglobin S, inhibiting polymerization. No information is available on the appearance of voxelotor in milk or on the safety of the drug in breastfed infants, but its low molecular weight of 337 Da indicates that it probably passes into milk. Because of the potential for serious adverse reactions in the infant, breastfeeding is currently not recommended during treatment and for at least 2 weeks after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is voxelotor?
Voxelotor is a medication that has been used to treat sickle cell disease (a condition that changes the shape of red blood cells). Sickle cell disease can cause issues such as pain, infections, and other health complications. Voxelotor is in a class of medication called hemoglobin S polymerization inhibitors. It is sold under the brand name Oxbryta®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take voxelotor. Can it make it harder for me to get pregnant?
It is not known if voxelotor can make it harder to get pregnant. However, having sickle cell disease may make it harder to get pregnant.
◈ Does taking voxelotor increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if voxelotor increases the chance for miscarriage. Sickle cell disease may increase the chance of miscarriage.
◈ Does taking voxelotor increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Data from animal studies suggest there is not an increased chance for birth defects when taking voxelotor during pregnancy. Studies have not been done to see if voxelotor increases the chance for birth defects in humans.
◈ Does taking voxelotor in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done in humans to see if voxelotor increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).People with sickle cell disease may have an increased chance of preterm delivery, low birth weight, and other pregnancy complications and should be monitored closely by healthcare providers during pregnancy.
◈ Does taking voxelotor in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if voxelotor can cause behavior or learning issues for the child.
◈ Breastfeeding while taking voxelotor:
There is no human data looking at the use of voxelotor in breastfeeding. The product label for voxelotor recommends people who are breastfeeding should not use this medication and should wait to breastfeed until 2 weeks after the last dose. But the benefit of using voxelotor may outweigh possible risks. Your healthcare providers can talk with you about using voxelotor and what treatment is best for you. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes voxelotor, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if voxelotor could affect male fertility or increase the chance of birth defects above the background risk. One experimental animal study suggested it might lower the chance of pregnancy when males take voxelotor, but this has not been checked in humans. Also, sickle cell disease itself may affect male fertility. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The protein binding of voxeletor is 99.8% _in vitro_.

[1]. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53.

[2]. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017;8(3):321-326.

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 [hydroxyurea], [L-glutamine], and [crizanlizumab] 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.
Voxelotor is a Hemoglobin S Polymerization Inhibitor. The mechanism of action of voxelotor is as a Hemoglobin S Polymerization Inhibitor, and Cytochrome P450 3A4 Inhibitor.
Voxelotor is an oral inhibitor of hemoglobin S polymerase that is used in the therapy of sickle cell disease. Voxelotor has been associated with rare instances of mild-to-moderate serum enzyme elevations during therapy, but has not been linked to instances of idiosyncratic acute liver injury.
Voxelotor is an orally bioavailable modulator and stabilizer of sickle cell hemoglobin (HbS), with potential use in the treatment of sickle cell disease (SCD). Upon administration, voxelotor targets and covalently binds to the N-terminal valine of the alpha chain of HbS. This stabilizes HbS, thereby improving oxygen binding affinity. The binding of voxelotor to HbS prevents HbS polymerization, reduces sickling, decreases red blood cell (RBC) damage and increases the half-life of RBCs. This improves blood flow and decreases hemolytic anemia.

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Drug Indication
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 [hydroxyurea].
Oxbryta is indicated for the treatment of haemolytic anaemia due to sickle cell disease (SCD) in adults and paediatric patients 12 years of age and older as monotherapy or in combination with hydroxycarbamide.
Treatment of sickle cell disease

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Mechanism of Action
Sickle cell disease is characterized by deoxygenated sickle hemoglobin (HbS) polymerization. The genetic mutation causing 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. Sickle-shaped red blood cells cannot effectively bind oxygen, thus incapable of allowing normal blood flow to organs. Voxelotor increases Hb oxygen affinity. It binds reversibly to hemoglobin (Hb) by forming a covalent bond with the N‐terminal valine of the α‐chain of the protein, resulting in an allosteric modification of Hb. Voxelotor stabilizes the oxygenated Hb state and prevents HbS polymerization by increasing hemoglobin’s affinity for oxygen.

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Pharmacodynamics
Voxelotor increases hemoglobin (Hb) oxygen affinity in a dose-dependent manner. It has led to up to a 40% increase in hemoglobin in clinical trials. Voxelotor may inhibit red blood cell sickling, attenuate red blood cell deformability, and reduce whole blood viscosity.

C19H19N3O3

337.37

337.142

1446321-46-5

71602803

Off-white to light brown solid powder

1.2±0.1 g/cm3

539.2±50.0 °C at 760 mmHg

80-82

279.9±30.1 °C

0.0±1.5 mmHg at 25°C

1.617

2.85

1

5

6

25

434

0

FWCVZAQENIZVMY-UHFFFAOYSA-N

InChI=1S/C19H19N3O3/c1-13(2)22-16(8-10-21-22)19-14(5-4-9-20-19)12-25-18-7-3-6-17(24)15(18)11-23/h3-11,13,24H,12H2,1-2H3

2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.41 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.17 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (6.17 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.08 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: 0.5 mg/mL (1.48 mM) in 1% DMSO + 99% Saline (add these co-solvents sequentially from left to right, and one by one),clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)